A 25-year-old woman presented with an exceedingly tender right ear. She’d had the helix of her ear pierced 3 days prior to presentation and 2 days after that, the ear had become tender. The tenderness was progressively worsening and associated with throbbing pain. The patient, who’d had her ears pierced before, was otherwise in good health and denied fever, chills, or travel outside of the country. She had been going to the gym regularly and took frequent showers. Physical examination revealed an erythematous swollen ear that was tender to the touch (FIGURE). The entire auricle was swollen except for the earlobe. The patient also reported purulent material draining from the helical piercing site.

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

Auricular perichondritis is an inflammation of the connective tissue surrounding the cartilage of the ear. Infectious and autoimmune factors may play a role. The underlying cartilage also may become involved. A useful clinical clue to the diagnosis of auricular perichondritis is sparing of the earlobe, which does not contain cartilage. Autoimmune causes typically have bilateral involvement. Infectious causes are usually associated with trauma and purulent drainage at the wound site. Ear piercings are an increasingly common cause, but perichondritis due to minor trauma, as a surgical complication, or in the absence of an obvious inciting trigger can occur. A careful history usually will reveal the cause.

In this case, the patient indicated that an open piercing gun at a shopping mall kiosk had been used to pierce her ear. Piercing with a sterile straight needle would have been preferable and less likely to be associated with secondary infection, as the shearing trauma to the perichondrium experienced with a piercing gun is thought to predispose to infection.¹ Exposure to fresh water from the shower could have been a source for Pseudomonas infection.¹

Differential: Pinpointing the diagnosis early is vital

A red and tender ear can raise a differential diagnosis that includes erysipelas, relapsing polychondritis, and auricular perichondritis. Erysipelas is a bacterial infection that spreads through the lymphatic system and is associated with intense and well-demarcated erythema. Erysipelas typically involves the face or lower legs. Infection after piercing or traumatic injury should raise suspicion of pseudomonal infection.^2-5 Untreated infection can spread quickly and lead to permanent ear deformity. Although the same pattern of inflammation can be seen in relapsing polychondritis, relapsing polychondritis typically involves both ears as well as the eyes and joints.

Prompt treatment is necessary to avoid cosmetic disfigurement

The timing of the reaction in our patient made infection obvious because Pseudomonas aeruginosa seems to have a particular affinity for damaged cartilage.²

Prompt treatment is necessary as infection can spread quickly and lead to cosmetic disfigurement.

Ciprofloxacin 500 mg twice daily is the treatment of choice. Although many skin infections can be empirically treated with oral cephalosporin, penicillin, or erythromycin, it is important to recognize that infected piercing sites and auricular perichondritis due to pseudomonal infection will not respond to these agents. That’s because these agents do not provide as good coverage for Pseudomonas as they do for Staphylococci or other bacteria more often associated with skin infection. Treatment with an agent such as amoxicillin and clavulanic acid or oral cephalexin can mean the loss of valuable time and subsequent cosmetic disfigurement.⁶

Continue to: When fluctuance is present...

When fluctuance is present, incision and drainage, or even debridement, may be necessary. When extensive infection leads to cartilage necrosis and liquefaction, treatment is difficult and may result in lasting disfigurement. Prompt empiric treatment currently is considered the best option.⁶

Our patient was prescribed a course of ciprofloxacin 500 mg every 12 hours for 10 days. She noted improvement within 2 days, and the infection resolved without complication.

CORRESPONDENCE
Matthew F. Helm, MD, Penn State Health Hershey Medical Center, 500 University Dr, HU14, Hershey, PA 17033; [email protected]

A 25-year-old woman presented with an exceedingly tender right ear. She’d had the helix of her ear pierced 3 days prior to presentation and 2 days after that, the ear had become tender. The tenderness was progressively worsening and associated with throbbing pain. The patient, who’d had her ears pierced before, was otherwise in good health and denied fever, chills, or travel outside of the country. She had been going to the gym regularly and took frequent showers. Physical examination revealed an erythematous swollen ear that was tender to the touch (FIGURE). The entire auricle was swollen except for the earlobe. The patient also reported purulent material draining from the helical piercing site.

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

Auricular perichondritis is an inflammation of the connective tissue surrounding the cartilage of the ear. Infectious and autoimmune factors may play a role. The underlying cartilage also may become involved. A useful clinical clue to the diagnosis of auricular perichondritis is sparing of the earlobe, which does not contain cartilage. Autoimmune causes typically have bilateral involvement. Infectious causes are usually associated with trauma and purulent drainage at the wound site. Ear piercings are an increasingly common cause, but perichondritis due to minor trauma, as a surgical complication, or in the absence of an obvious inciting trigger can occur. A careful history usually will reveal the cause.

In this case, the patient indicated that an open piercing gun at a shopping mall kiosk had been used to pierce her ear. Piercing with a sterile straight needle would have been preferable and less likely to be associated with secondary infection, as the shearing trauma to the perichondrium experienced with a piercing gun is thought to predispose to infection.¹ Exposure to fresh water from the shower could have been a source for Pseudomonas infection.¹

Differential: Pinpointing the diagnosis early is vital

A red and tender ear can raise a differential diagnosis that includes erysipelas, relapsing polychondritis, and auricular perichondritis. Erysipelas is a bacterial infection that spreads through the lymphatic system and is associated with intense and well-demarcated erythema. Erysipelas typically involves the face or lower legs. Infection after piercing or traumatic injury should raise suspicion of pseudomonal infection.^2-5 Untreated infection can spread quickly and lead to permanent ear deformity. Although the same pattern of inflammation can be seen in relapsing polychondritis, relapsing polychondritis typically involves both ears as well as the eyes and joints.

Prompt treatment is necessary to avoid cosmetic disfigurement

The timing of the reaction in our patient made infection obvious because Pseudomonas aeruginosa seems to have a particular affinity for damaged cartilage.²

Prompt treatment is necessary as infection can spread quickly and lead to cosmetic disfigurement.

Ciprofloxacin 500 mg twice daily is the treatment of choice. Although many skin infections can be empirically treated with oral cephalosporin, penicillin, or erythromycin, it is important to recognize that infected piercing sites and auricular perichondritis due to pseudomonal infection will not respond to these agents. That’s because these agents do not provide as good coverage for Pseudomonas as they do for Staphylococci or other bacteria more often associated with skin infection. Treatment with an agent such as amoxicillin and clavulanic acid or oral cephalexin can mean the loss of valuable time and subsequent cosmetic disfigurement.⁶

Continue to: When fluctuance is present...

When fluctuance is present, incision and drainage, or even debridement, may be necessary. When extensive infection leads to cartilage necrosis and liquefaction, treatment is difficult and may result in lasting disfigurement. Prompt empiric treatment currently is considered the best option.⁶

Our patient was prescribed a course of ciprofloxacin 500 mg every 12 hours for 10 days. She noted improvement within 2 days, and the infection resolved without complication.

CORRESPONDENCE
Matthew F. Helm, MD, Penn State Health Hershey Medical Center, 500 University Dr, HU14, Hershey, PA 17033; [email protected]

A 25-year-old woman presented with an exceedingly tender right ear. She’d had the helix of her ear pierced 3 days prior to presentation and 2 days after that, the ear had become tender. The tenderness was progressively worsening and associated with throbbing pain. The patient, who’d had her ears pierced before, was otherwise in good health and denied fever, chills, or travel outside of the country. She had been going to the gym regularly and took frequent showers. Physical examination revealed an erythematous swollen ear that was tender to the touch (FIGURE). The entire auricle was swollen except for the earlobe. The patient also reported purulent material draining from the helical piercing site.

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

Auricular perichondritis is an inflammation of the connective tissue surrounding the cartilage of the ear. Infectious and autoimmune factors may play a role. The underlying cartilage also may become involved. A useful clinical clue to the diagnosis of auricular perichondritis is sparing of the earlobe, which does not contain cartilage. Autoimmune causes typically have bilateral involvement. Infectious causes are usually associated with trauma and purulent drainage at the wound site. Ear piercings are an increasingly common cause, but perichondritis due to minor trauma, as a surgical complication, or in the absence of an obvious inciting trigger can occur. A careful history usually will reveal the cause.

In this case, the patient indicated that an open piercing gun at a shopping mall kiosk had been used to pierce her ear. Piercing with a sterile straight needle would have been preferable and less likely to be associated with secondary infection, as the shearing trauma to the perichondrium experienced with a piercing gun is thought to predispose to infection.¹ Exposure to fresh water from the shower could have been a source for Pseudomonas infection.¹

Differential: Pinpointing the diagnosis early is vital

A red and tender ear can raise a differential diagnosis that includes erysipelas, relapsing polychondritis, and auricular perichondritis. Erysipelas is a bacterial infection that spreads through the lymphatic system and is associated with intense and well-demarcated erythema. Erysipelas typically involves the face or lower legs. Infection after piercing or traumatic injury should raise suspicion of pseudomonal infection.^2-5 Untreated infection can spread quickly and lead to permanent ear deformity. Although the same pattern of inflammation can be seen in relapsing polychondritis, relapsing polychondritis typically involves both ears as well as the eyes and joints.

Prompt treatment is necessary to avoid cosmetic disfigurement

The timing of the reaction in our patient made infection obvious because Pseudomonas aeruginosa seems to have a particular affinity for damaged cartilage.²

Prompt treatment is necessary as infection can spread quickly and lead to cosmetic disfigurement.

Ciprofloxacin 500 mg twice daily is the treatment of choice. Although many skin infections can be empirically treated with oral cephalosporin, penicillin, or erythromycin, it is important to recognize that infected piercing sites and auricular perichondritis due to pseudomonal infection will not respond to these agents. That’s because these agents do not provide as good coverage for Pseudomonas as they do for Staphylococci or other bacteria more often associated with skin infection. Treatment with an agent such as amoxicillin and clavulanic acid or oral cephalexin can mean the loss of valuable time and subsequent cosmetic disfigurement.⁶

Continue to: When fluctuance is present...

When fluctuance is present, incision and drainage, or even debridement, may be necessary. When extensive infection leads to cartilage necrosis and liquefaction, treatment is difficult and may result in lasting disfigurement. Prompt empiric treatment currently is considered the best option.⁶

Our patient was prescribed a course of ciprofloxacin 500 mg every 12 hours for 10 days. She noted improvement within 2 days, and the infection resolved without complication.

CORRESPONDENCE
Matthew F. Helm, MD, Penn State Health Hershey Medical Center, 500 University Dr, HU14, Hershey, PA 17033; [email protected]

THE CASE

A primiparous mother gave birth to a girl at 38 and 4/7 weeks via uncomplicated vaginal delivery. Prenatal labs were normal. Neonatal physical examination was normal and the child’s birth weight was in the 33rd percentile. APGAR scores were 8 and 9. The neonate was afebrile during hospitalization, with a heart rate of 120 to 150 beats/min and a respiratory rate of 30 to 48 breaths/min. Her preductal and postductal oxygen saturations were 100% and 98%, respectively. She was discharged on Day 2 of life, having lost only 3% of her birth weight.

The patient was seen in clinic on Day 6 of life for a well-child exam and was in the 17th percentile for weight. At another visit for a well-child exam on Day 14 of life, she had not fully regained her birth weight. At both visits, the mother reported no issues with breastfeeding and said she was supplementing with formula. The patient was seen again for follow-up on Days 16 and 21 of life and demonstrated no weight gain despite close follow-up with the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC), which determined the newborn had some breastfeeding issues but seemed to be consuming adequate calories. However, WIC assessments revealed that during feeding, the child was expending too many calories and had nasal congestion. The patient was admitted to the hospital on Day 21 of life with a diagnosis of failure to thrive (FTT), at which point she was in the 12th percentile for weight.

THE DIAGNOSIS

Shortly after the infant was admitted, she showed signs of respiratory distress. On physical examination, the on-call resident noted intermittent retractions with inspiratory stridor, and the patient demonstrated intermittent severe oxygen desaturations into the 70s. She also was sucking her pacifier furiously, which appeared to provide some relief from the respiratory distress. The child’s parents noted that she had demonstrated intermittent periods of respiratory distress since shortly after birth that seemed to be increasing in frequency.

Upon careful examination, the on-call resident identified a cystic lesion at the base of the child’s tongue. The otolaryngologist on call was brought in for an urgent consultation but was unable to visualize the lesion on physical examination and did not recommend further intervention at that time. The patient continued to demonstrate respiratory distress with hypoxia and was transferred to the pediatric intensive care unit for close monitoring.

The next morning a second otolaryngology consultation was requested. A computed tomography scan of the neck demonstrated a 1.5-cm cystic-appearing mass at the base of the tongue that was obstructing the patient’s airway. Direct flexible bronchoscopy confirmed the radiographic findings. The patient underwent immediate surgical resection of the lesion using a laser. A clear and milky gray cystic fluid exuded from the cyst when the lesion was pierced. The otolaryngologist visualized a widely patent airway following excision of the lesion (FIGURE).

Pathology results revealed no evidence of malignancy. The final diagnosis was a simple base-of-tongue cyst.

DISCUSSION

Failure to thrive is common in neonates and occurs most often due to inadequate caloric intake; however, it also can be caused by systemic disease associated with inadequate gastrointestinal absorption or increased caloric expenditure, such as congenital heart disease, renal disease (eg, renal tubular acidosis), chronic pulmonary disease (eg, cystic fibrosis), laryngomalacia, malignancy, immunodeficiency, or thyroid disease.¹

Continue to: Respiratory distress

Respiratory distress in neonates also is common but tends to occur shortly after birth.² Conditions associated with respiratory distress in neonates include transient tachypnea of the newborn, respiratory distress syndrome, pneumothorax, persistent pulmonary hypertension of the newborn, pneumonia, and meconium aspiration syndrome.² Interestingly, there are additional reports in the literature of FTT and respiratory distress in neonates caused by obstructive pharyngeal lesions.^3-5

Mechanical obstruction should be considered in neonates with failure to thrive and respiratory distress.

Base-of-tongue cysts are rare in infants. Fewer than 50 cases were reported prior to 2011, with many being described as asymptomatic nonpainful lesions.⁶ Given the anatomic location of base-of-tongue cysts, the differential diagnosis should also include mucoceles, thyroglossal duct cysts, dermoid cysts, epidermoid cysts, vallecular cysts, hemangiomas, cystic hygromas, lymphangiomas, thyroid remnant cysts, teratomas, and hamartomas.^4,7,8 When tongue cysts are initially discovered, inspiratory stridor, FTT, swallowing deficits, oxygen desaturation, respiratory failure, and/or acute life-threatening events have been reported.^6,9,10

One important clinical observation made in our case was the use of an external apparatus to relieve the neonate’s respiratory distress. During physical examination, the on-call resident noted the patient was furiously sucking her pacifier, which seemed to reduce the respiratory difficulty and desaturations. It is known that non-nutritive sucking (NNS) can provide provisions for stress relief, improve oxygenation, and provide proprioceptive positioning of key anatomical structures within the oral cavity.¹¹ Without the use of an external apparatus like a pacifier during restful states, neonates may develop vacuum-glossoptosis syndrome, in which the dorsum of the tongue and the soft palate adhere to the posterior pharyngeal wall and obstruct the airway.¹² Our patient may have used the pacifier as an NNS task to move the tongue forward and break the glossoptosis-pharyngeal seal by sucking hard and fast during periods of respiratory distress, which reduced the potential for a vacuum-glossoptosis phenomenon that was likely created by the cyst during restful states.

Our patient was seen in clinic for follow-up after surgery on Day 35 of life. She was thriving and her weight was in the 24th percentile. She was seen again on Day 67 of life for a well-child exam and was in the 43rd percentile for weight.

THE TAKEAWAY

Non-nutritive sucking with a pacifier may relieve airway obstruction caused by base-of-tongue cysts.

There is a sizeable list of possible diagnoses to consider when a neonate presents with FTT and respiratory distress. It is important to consider mechanical obstruction as a possible diagnosis and one which, if identified early, may be lifesaving. Our case demonstrates a proposed mechanism by which a mechanical obstruction such as a base-of-tongue cyst can cause the vacuum-glossoptosis syndrome; it also highlights NNS as a potential means of overcoming this phenomenon.

CORRESPONDENCE
Benjamin P. Hansen, MD, Renown Medical Group, 4796 Caughlin Pkwy, Ste 108, Reno, NV 89519; [email protected]

THE CASE

A primiparous mother gave birth to a girl at 38 and 4/7 weeks via uncomplicated vaginal delivery. Prenatal labs were normal. Neonatal physical examination was normal and the child’s birth weight was in the 33rd percentile. APGAR scores were 8 and 9. The neonate was afebrile during hospitalization, with a heart rate of 120 to 150 beats/min and a respiratory rate of 30 to 48 breaths/min. Her preductal and postductal oxygen saturations were 100% and 98%, respectively. She was discharged on Day 2 of life, having lost only 3% of her birth weight.

The patient was seen in clinic on Day 6 of life for a well-child exam and was in the 17th percentile for weight. At another visit for a well-child exam on Day 14 of life, she had not fully regained her birth weight. At both visits, the mother reported no issues with breastfeeding and said she was supplementing with formula. The patient was seen again for follow-up on Days 16 and 21 of life and demonstrated no weight gain despite close follow-up with the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC), which determined the newborn had some breastfeeding issues but seemed to be consuming adequate calories. However, WIC assessments revealed that during feeding, the child was expending too many calories and had nasal congestion. The patient was admitted to the hospital on Day 21 of life with a diagnosis of failure to thrive (FTT), at which point she was in the 12th percentile for weight.

THE DIAGNOSIS

Shortly after the infant was admitted, she showed signs of respiratory distress. On physical examination, the on-call resident noted intermittent retractions with inspiratory stridor, and the patient demonstrated intermittent severe oxygen desaturations into the 70s. She also was sucking her pacifier furiously, which appeared to provide some relief from the respiratory distress. The child’s parents noted that she had demonstrated intermittent periods of respiratory distress since shortly after birth that seemed to be increasing in frequency.

Upon careful examination, the on-call resident identified a cystic lesion at the base of the child’s tongue. The otolaryngologist on call was brought in for an urgent consultation but was unable to visualize the lesion on physical examination and did not recommend further intervention at that time. The patient continued to demonstrate respiratory distress with hypoxia and was transferred to the pediatric intensive care unit for close monitoring.

The next morning a second otolaryngology consultation was requested. A computed tomography scan of the neck demonstrated a 1.5-cm cystic-appearing mass at the base of the tongue that was obstructing the patient’s airway. Direct flexible bronchoscopy confirmed the radiographic findings. The patient underwent immediate surgical resection of the lesion using a laser. A clear and milky gray cystic fluid exuded from the cyst when the lesion was pierced. The otolaryngologist visualized a widely patent airway following excision of the lesion (FIGURE).

Pathology results revealed no evidence of malignancy. The final diagnosis was a simple base-of-tongue cyst.

DISCUSSION

Failure to thrive is common in neonates and occurs most often due to inadequate caloric intake; however, it also can be caused by systemic disease associated with inadequate gastrointestinal absorption or increased caloric expenditure, such as congenital heart disease, renal disease (eg, renal tubular acidosis), chronic pulmonary disease (eg, cystic fibrosis), laryngomalacia, malignancy, immunodeficiency, or thyroid disease.¹

Continue to: Respiratory distress

Respiratory distress in neonates also is common but tends to occur shortly after birth.² Conditions associated with respiratory distress in neonates include transient tachypnea of the newborn, respiratory distress syndrome, pneumothorax, persistent pulmonary hypertension of the newborn, pneumonia, and meconium aspiration syndrome.² Interestingly, there are additional reports in the literature of FTT and respiratory distress in neonates caused by obstructive pharyngeal lesions.^3-5

Mechanical obstruction should be considered in neonates with failure to thrive and respiratory distress.

Base-of-tongue cysts are rare in infants. Fewer than 50 cases were reported prior to 2011, with many being described as asymptomatic nonpainful lesions.⁶ Given the anatomic location of base-of-tongue cysts, the differential diagnosis should also include mucoceles, thyroglossal duct cysts, dermoid cysts, epidermoid cysts, vallecular cysts, hemangiomas, cystic hygromas, lymphangiomas, thyroid remnant cysts, teratomas, and hamartomas.^4,7,8 When tongue cysts are initially discovered, inspiratory stridor, FTT, swallowing deficits, oxygen desaturation, respiratory failure, and/or acute life-threatening events have been reported.^6,9,10

One important clinical observation made in our case was the use of an external apparatus to relieve the neonate’s respiratory distress. During physical examination, the on-call resident noted the patient was furiously sucking her pacifier, which seemed to reduce the respiratory difficulty and desaturations. It is known that non-nutritive sucking (NNS) can provide provisions for stress relief, improve oxygenation, and provide proprioceptive positioning of key anatomical structures within the oral cavity.¹¹ Without the use of an external apparatus like a pacifier during restful states, neonates may develop vacuum-glossoptosis syndrome, in which the dorsum of the tongue and the soft palate adhere to the posterior pharyngeal wall and obstruct the airway.¹² Our patient may have used the pacifier as an NNS task to move the tongue forward and break the glossoptosis-pharyngeal seal by sucking hard and fast during periods of respiratory distress, which reduced the potential for a vacuum-glossoptosis phenomenon that was likely created by the cyst during restful states.

Our patient was seen in clinic for follow-up after surgery on Day 35 of life. She was thriving and her weight was in the 24th percentile. She was seen again on Day 67 of life for a well-child exam and was in the 43rd percentile for weight.

THE TAKEAWAY

Non-nutritive sucking with a pacifier may relieve airway obstruction caused by base-of-tongue cysts.

There is a sizeable list of possible diagnoses to consider when a neonate presents with FTT and respiratory distress. It is important to consider mechanical obstruction as a possible diagnosis and one which, if identified early, may be lifesaving. Our case demonstrates a proposed mechanism by which a mechanical obstruction such as a base-of-tongue cyst can cause the vacuum-glossoptosis syndrome; it also highlights NNS as a potential means of overcoming this phenomenon.

CORRESPONDENCE
Benjamin P. Hansen, MD, Renown Medical Group, 4796 Caughlin Pkwy, Ste 108, Reno, NV 89519; [email protected]

THE CASE

A primiparous mother gave birth to a girl at 38 and 4/7 weeks via uncomplicated vaginal delivery. Prenatal labs were normal. Neonatal physical examination was normal and the child’s birth weight was in the 33rd percentile. APGAR scores were 8 and 9. The neonate was afebrile during hospitalization, with a heart rate of 120 to 150 beats/min and a respiratory rate of 30 to 48 breaths/min. Her preductal and postductal oxygen saturations were 100% and 98%, respectively. She was discharged on Day 2 of life, having lost only 3% of her birth weight.

The patient was seen in clinic on Day 6 of life for a well-child exam and was in the 17th percentile for weight. At another visit for a well-child exam on Day 14 of life, she had not fully regained her birth weight. At both visits, the mother reported no issues with breastfeeding and said she was supplementing with formula. The patient was seen again for follow-up on Days 16 and 21 of life and demonstrated no weight gain despite close follow-up with the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC), which determined the newborn had some breastfeeding issues but seemed to be consuming adequate calories. However, WIC assessments revealed that during feeding, the child was expending too many calories and had nasal congestion. The patient was admitted to the hospital on Day 21 of life with a diagnosis of failure to thrive (FTT), at which point she was in the 12th percentile for weight.

THE DIAGNOSIS

Shortly after the infant was admitted, she showed signs of respiratory distress. On physical examination, the on-call resident noted intermittent retractions with inspiratory stridor, and the patient demonstrated intermittent severe oxygen desaturations into the 70s. She also was sucking her pacifier furiously, which appeared to provide some relief from the respiratory distress. The child’s parents noted that she had demonstrated intermittent periods of respiratory distress since shortly after birth that seemed to be increasing in frequency.

Upon careful examination, the on-call resident identified a cystic lesion at the base of the child’s tongue. The otolaryngologist on call was brought in for an urgent consultation but was unable to visualize the lesion on physical examination and did not recommend further intervention at that time. The patient continued to demonstrate respiratory distress with hypoxia and was transferred to the pediatric intensive care unit for close monitoring.

The next morning a second otolaryngology consultation was requested. A computed tomography scan of the neck demonstrated a 1.5-cm cystic-appearing mass at the base of the tongue that was obstructing the patient’s airway. Direct flexible bronchoscopy confirmed the radiographic findings. The patient underwent immediate surgical resection of the lesion using a laser. A clear and milky gray cystic fluid exuded from the cyst when the lesion was pierced. The otolaryngologist visualized a widely patent airway following excision of the lesion (FIGURE).

Pathology results revealed no evidence of malignancy. The final diagnosis was a simple base-of-tongue cyst.

DISCUSSION

Failure to thrive is common in neonates and occurs most often due to inadequate caloric intake; however, it also can be caused by systemic disease associated with inadequate gastrointestinal absorption or increased caloric expenditure, such as congenital heart disease, renal disease (eg, renal tubular acidosis), chronic pulmonary disease (eg, cystic fibrosis), laryngomalacia, malignancy, immunodeficiency, or thyroid disease.¹

Continue to: Respiratory distress

Respiratory distress in neonates also is common but tends to occur shortly after birth.² Conditions associated with respiratory distress in neonates include transient tachypnea of the newborn, respiratory distress syndrome, pneumothorax, persistent pulmonary hypertension of the newborn, pneumonia, and meconium aspiration syndrome.² Interestingly, there are additional reports in the literature of FTT and respiratory distress in neonates caused by obstructive pharyngeal lesions.^3-5

Mechanical obstruction should be considered in neonates with failure to thrive and respiratory distress.

Base-of-tongue cysts are rare in infants. Fewer than 50 cases were reported prior to 2011, with many being described as asymptomatic nonpainful lesions.⁶ Given the anatomic location of base-of-tongue cysts, the differential diagnosis should also include mucoceles, thyroglossal duct cysts, dermoid cysts, epidermoid cysts, vallecular cysts, hemangiomas, cystic hygromas, lymphangiomas, thyroid remnant cysts, teratomas, and hamartomas.^4,7,8 When tongue cysts are initially discovered, inspiratory stridor, FTT, swallowing deficits, oxygen desaturation, respiratory failure, and/or acute life-threatening events have been reported.^6,9,10

One important clinical observation made in our case was the use of an external apparatus to relieve the neonate’s respiratory distress. During physical examination, the on-call resident noted the patient was furiously sucking her pacifier, which seemed to reduce the respiratory difficulty and desaturations. It is known that non-nutritive sucking (NNS) can provide provisions for stress relief, improve oxygenation, and provide proprioceptive positioning of key anatomical structures within the oral cavity.¹¹ Without the use of an external apparatus like a pacifier during restful states, neonates may develop vacuum-glossoptosis syndrome, in which the dorsum of the tongue and the soft palate adhere to the posterior pharyngeal wall and obstruct the airway.¹² Our patient may have used the pacifier as an NNS task to move the tongue forward and break the glossoptosis-pharyngeal seal by sucking hard and fast during periods of respiratory distress, which reduced the potential for a vacuum-glossoptosis phenomenon that was likely created by the cyst during restful states.

Our patient was seen in clinic for follow-up after surgery on Day 35 of life. She was thriving and her weight was in the 24th percentile. She was seen again on Day 67 of life for a well-child exam and was in the 43rd percentile for weight.

THE TAKEAWAY

Non-nutritive sucking with a pacifier may relieve airway obstruction caused by base-of-tongue cysts.

There is a sizeable list of possible diagnoses to consider when a neonate presents with FTT and respiratory distress. It is important to consider mechanical obstruction as a possible diagnosis and one which, if identified early, may be lifesaving. Our case demonstrates a proposed mechanism by which a mechanical obstruction such as a base-of-tongue cyst can cause the vacuum-glossoptosis syndrome; it also highlights NNS as a potential means of overcoming this phenomenon.

CORRESPONDENCE
Benjamin P. Hansen, MD, Renown Medical Group, 4796 Caughlin Pkwy, Ste 108, Reno, NV 89519; [email protected]

ILLUSTRATIVE CASE

Ms. M is a 55-year-old woman who is generally healthy, but who was diagnosed recently with severe vitamin D deficiency (serum 25-hydroxyvitamin D level of 8 ng/mL). She is being seen for her second episode of acute viral bronchitis in the past 6 months. She has no significant smoking or exposure history, no history of asthma, and takes no respiratory medications. Standard treatment for her level of vitamin D deficiency is 50,000 IU/week in bolus dosing, but is that your best option in this case?

Acute respiratory tract infections (ARTIs) include nonspecific upper respiratory illnesses, otitis media, sinusitis (~70% viral), pharyngitis, acute bronchitis (also ~70% viral), influenza, respiratory syncytial virus, and pneumonia.^1,2 In the United States, ARTIs strain the health care system and are the most common cause of ambulatory care visits, accounting for almost 120 million, or about 10% of all visits, per year.³ In addition, ARTIs account for almost 50% of antibiotic prescriptions for adults and almost 75% of antibiotic prescriptions for children—many of which are unnecessary.^2,4

While patient and parent education, antibiotic stewardship programs, and demand management may reduce inappropriate antibiotic use and the overall burden of ARTIs on the health care system, prevention of infections is a powerful tool within the overall approach to managing ARTIs.

STUDY SUMMARY

Vitamin D protects against ARTIs, but only in smaller doses

This 2017 systematic review and meta-analysis of 25 trials (N=10,933) evaluated vitamin D supplementation for the prevention of ARTIs in the primary care setting. Individual participant data were reevaluated to reduce risk of bias. The Cochrane risk of bias tool was used to address threats to validity.

The review and meta-analysis included institutional review board–approved, randomized, double-blind, placebo-controlled trials of vitamin D₃ or vitamin D₂ supplementation of any duration and in any language. The incidence of ARTI was a prespecified efficacy outcome. Duration of the included randomized controlled trials (RCTs) ranged from 7 weeks to 1.5 years.

Outcomes. The primary outcome was an incidence of at least 1 ARTI. Secondary outcomes included incidence of upper and lower ARTIs; incidence of adverse reactions to vitamin D; incidence of emergency department visits or hospital admission or both for ARTI; use of antimicrobials for ARTI; absence from work or school due to ARTI, and mortality (ARTI-related and all-cause).

Findings. Daily or weekly vitamin D supplementation (in doses ranging from < 20 to ≥ 50 µg/d) reduced the risk for ARTI (adjusted odds ratio [AOR] = 0.88; 95% confidence interval [CI], 0.81-0.96; number needed to treat [NNT] = 33). In subgroup analysis, daily or weekly vitamin D was protective (AOR = 0.81; 95% CI, 0.72-0.91), but bolus dosing (≥ 30,000 IU) was not (AOR = 0.97; 95% CI, 0.86-1.10).

Continue to: In 2-step analysis...

This study found that low-dose daily or weekly vitamin D supplementation was protective against acute respiratory tract infections, but bolus dosing was not.

In 2-step analysis, patients benefited who: had baseline circulating 25-hydroxyvitamin D concentrations < 10 ng/mL (AOR = 0.30; 95% CI, 0.17-0.53; NNT = 4); had baseline circulating 25-hydroxyvitamin D levels of 10 to 28 ng/mL (AOR = 0.75; 95% CI, 0.60-0.95; NNT = 15); were ages 1.1 to 15.9 years (AOR = 0.59; 95% CI, 0.45-0.79); were ages 16 to 65 years (AOR = 0.79; 95% CI, 0.63-0.99); or had a body mass index < 25 (AOR = 0.82; 95% CI, 0.71-0.95).

Higher D levels are a different story. Vitamin D supplementation in people with circulating levels of 25-hydroxyvitamin D ≥ 30 ng/mL did not appear to provide benefit (AOR = 0.96; 95% CI, 0.78-1.18). Supplementation in this population did not influence any of the secondary outcomes, including risk for all-cause serious adverse events (AOR = 0.98; 95% CI, 0.80-1.20).

WHAT’S NEW

A more accurate snapshot

Previous studies of vitamin D and respiratory tract infections were mostly observational in nature. Those that were RCTs used variable doses of vitamin D, had variable baseline 25-hydroxyvitamin D levels, and employed various methods to monitor ARTI symptoms/incidence.^5-8 This is the first systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials with supplementation using vitamin D₃ or vitamin D₂ that used individual participant-level data, which gives a more accurate estimate of outcomes when compared with traditional meta-analyses.

CAVEATS

Only the most deficient benefit?

Vitamin D supplementation was safe and protected against ARTIs overall, but the greatest effect of vitamin D supplementation on the prevention of ARTIs was noted in those who were most severely vitamin D deficient (those with circulating 25-hydroxyvitamin levels < 10 ng/mL, NNT = 4; 10-28 ng/mL, NNT = 15). There was no demonstrable effect once circulating 25-hydroxyvitamin D levels reached 30 ng/mL.

CHALLENGES TO IMPLEMENTATION

Breaking tradition

The study found that both daily and weekly doses of vitamin D were effective in reducing the incidence of ARTIs, but the doses used were much lower than the commonly used 10,000 to 50,000 IU bolus doses, which were ineffective in reducing ARTIs in the current meta-analysis. Since bolus dosing is an ingrained practice for many providers, changing this may prove challenging.

Continue to: In addition...

In addition, the authors of the study suggest that one of the ways to provide this level of vitamin D is through food fortification, but food fortification is often complicated by emotional and/or political issues that could thwart implementation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

Ms. M is a 55-year-old woman who is generally healthy, but who was diagnosed recently with severe vitamin D deficiency (serum 25-hydroxyvitamin D level of 8 ng/mL). She is being seen for her second episode of acute viral bronchitis in the past 6 months. She has no significant smoking or exposure history, no history of asthma, and takes no respiratory medications. Standard treatment for her level of vitamin D deficiency is 50,000 IU/week in bolus dosing, but is that your best option in this case?

Acute respiratory tract infections (ARTIs) include nonspecific upper respiratory illnesses, otitis media, sinusitis (~70% viral), pharyngitis, acute bronchitis (also ~70% viral), influenza, respiratory syncytial virus, and pneumonia.^1,2 In the United States, ARTIs strain the health care system and are the most common cause of ambulatory care visits, accounting for almost 120 million, or about 10% of all visits, per year.³ In addition, ARTIs account for almost 50% of antibiotic prescriptions for adults and almost 75% of antibiotic prescriptions for children—many of which are unnecessary.^2,4

While patient and parent education, antibiotic stewardship programs, and demand management may reduce inappropriate antibiotic use and the overall burden of ARTIs on the health care system, prevention of infections is a powerful tool within the overall approach to managing ARTIs.

STUDY SUMMARY

Vitamin D protects against ARTIs, but only in smaller doses

This 2017 systematic review and meta-analysis of 25 trials (N=10,933) evaluated vitamin D supplementation for the prevention of ARTIs in the primary care setting. Individual participant data were reevaluated to reduce risk of bias. The Cochrane risk of bias tool was used to address threats to validity.

The review and meta-analysis included institutional review board–approved, randomized, double-blind, placebo-controlled trials of vitamin D₃ or vitamin D₂ supplementation of any duration and in any language. The incidence of ARTI was a prespecified efficacy outcome. Duration of the included randomized controlled trials (RCTs) ranged from 7 weeks to 1.5 years.

Outcomes. The primary outcome was an incidence of at least 1 ARTI. Secondary outcomes included incidence of upper and lower ARTIs; incidence of adverse reactions to vitamin D; incidence of emergency department visits or hospital admission or both for ARTI; use of antimicrobials for ARTI; absence from work or school due to ARTI, and mortality (ARTI-related and all-cause).

Findings. Daily or weekly vitamin D supplementation (in doses ranging from < 20 to ≥ 50 µg/d) reduced the risk for ARTI (adjusted odds ratio [AOR] = 0.88; 95% confidence interval [CI], 0.81-0.96; number needed to treat [NNT] = 33). In subgroup analysis, daily or weekly vitamin D was protective (AOR = 0.81; 95% CI, 0.72-0.91), but bolus dosing (≥ 30,000 IU) was not (AOR = 0.97; 95% CI, 0.86-1.10).

Continue to: In 2-step analysis...

This study found that low-dose daily or weekly vitamin D supplementation was protective against acute respiratory tract infections, but bolus dosing was not.

In 2-step analysis, patients benefited who: had baseline circulating 25-hydroxyvitamin D concentrations < 10 ng/mL (AOR = 0.30; 95% CI, 0.17-0.53; NNT = 4); had baseline circulating 25-hydroxyvitamin D levels of 10 to 28 ng/mL (AOR = 0.75; 95% CI, 0.60-0.95; NNT = 15); were ages 1.1 to 15.9 years (AOR = 0.59; 95% CI, 0.45-0.79); were ages 16 to 65 years (AOR = 0.79; 95% CI, 0.63-0.99); or had a body mass index < 25 (AOR = 0.82; 95% CI, 0.71-0.95).

Higher D levels are a different story. Vitamin D supplementation in people with circulating levels of 25-hydroxyvitamin D ≥ 30 ng/mL did not appear to provide benefit (AOR = 0.96; 95% CI, 0.78-1.18). Supplementation in this population did not influence any of the secondary outcomes, including risk for all-cause serious adverse events (AOR = 0.98; 95% CI, 0.80-1.20).

WHAT’S NEW

A more accurate snapshot

Previous studies of vitamin D and respiratory tract infections were mostly observational in nature. Those that were RCTs used variable doses of vitamin D, had variable baseline 25-hydroxyvitamin D levels, and employed various methods to monitor ARTI symptoms/incidence.^5-8 This is the first systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials with supplementation using vitamin D₃ or vitamin D₂ that used individual participant-level data, which gives a more accurate estimate of outcomes when compared with traditional meta-analyses.

CAVEATS

Only the most deficient benefit?

Vitamin D supplementation was safe and protected against ARTIs overall, but the greatest effect of vitamin D supplementation on the prevention of ARTIs was noted in those who were most severely vitamin D deficient (those with circulating 25-hydroxyvitamin levels < 10 ng/mL, NNT = 4; 10-28 ng/mL, NNT = 15). There was no demonstrable effect once circulating 25-hydroxyvitamin D levels reached 30 ng/mL.

CHALLENGES TO IMPLEMENTATION

Breaking tradition

The study found that both daily and weekly doses of vitamin D were effective in reducing the incidence of ARTIs, but the doses used were much lower than the commonly used 10,000 to 50,000 IU bolus doses, which were ineffective in reducing ARTIs in the current meta-analysis. Since bolus dosing is an ingrained practice for many providers, changing this may prove challenging.

Continue to: In addition...

In addition, the authors of the study suggest that one of the ways to provide this level of vitamin D is through food fortification, but food fortification is often complicated by emotional and/or political issues that could thwart implementation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

Ms. M is a 55-year-old woman who is generally healthy, but who was diagnosed recently with severe vitamin D deficiency (serum 25-hydroxyvitamin D level of 8 ng/mL). She is being seen for her second episode of acute viral bronchitis in the past 6 months. She has no significant smoking or exposure history, no history of asthma, and takes no respiratory medications. Standard treatment for her level of vitamin D deficiency is 50,000 IU/week in bolus dosing, but is that your best option in this case?

Acute respiratory tract infections (ARTIs) include nonspecific upper respiratory illnesses, otitis media, sinusitis (~70% viral), pharyngitis, acute bronchitis (also ~70% viral), influenza, respiratory syncytial virus, and pneumonia.^1,2 In the United States, ARTIs strain the health care system and are the most common cause of ambulatory care visits, accounting for almost 120 million, or about 10% of all visits, per year.³ In addition, ARTIs account for almost 50% of antibiotic prescriptions for adults and almost 75% of antibiotic prescriptions for children—many of which are unnecessary.^2,4

While patient and parent education, antibiotic stewardship programs, and demand management may reduce inappropriate antibiotic use and the overall burden of ARTIs on the health care system, prevention of infections is a powerful tool within the overall approach to managing ARTIs.

STUDY SUMMARY

Vitamin D protects against ARTIs, but only in smaller doses

This 2017 systematic review and meta-analysis of 25 trials (N=10,933) evaluated vitamin D supplementation for the prevention of ARTIs in the primary care setting. Individual participant data were reevaluated to reduce risk of bias. The Cochrane risk of bias tool was used to address threats to validity.

The review and meta-analysis included institutional review board–approved, randomized, double-blind, placebo-controlled trials of vitamin D₃ or vitamin D₂ supplementation of any duration and in any language. The incidence of ARTI was a prespecified efficacy outcome. Duration of the included randomized controlled trials (RCTs) ranged from 7 weeks to 1.5 years.

Outcomes. The primary outcome was an incidence of at least 1 ARTI. Secondary outcomes included incidence of upper and lower ARTIs; incidence of adverse reactions to vitamin D; incidence of emergency department visits or hospital admission or both for ARTI; use of antimicrobials for ARTI; absence from work or school due to ARTI, and mortality (ARTI-related and all-cause).

Findings. Daily or weekly vitamin D supplementation (in doses ranging from < 20 to ≥ 50 µg/d) reduced the risk for ARTI (adjusted odds ratio [AOR] = 0.88; 95% confidence interval [CI], 0.81-0.96; number needed to treat [NNT] = 33). In subgroup analysis, daily or weekly vitamin D was protective (AOR = 0.81; 95% CI, 0.72-0.91), but bolus dosing (≥ 30,000 IU) was not (AOR = 0.97; 95% CI, 0.86-1.10).

Continue to: In 2-step analysis...

This study found that low-dose daily or weekly vitamin D supplementation was protective against acute respiratory tract infections, but bolus dosing was not.

In 2-step analysis, patients benefited who: had baseline circulating 25-hydroxyvitamin D concentrations < 10 ng/mL (AOR = 0.30; 95% CI, 0.17-0.53; NNT = 4); had baseline circulating 25-hydroxyvitamin D levels of 10 to 28 ng/mL (AOR = 0.75; 95% CI, 0.60-0.95; NNT = 15); were ages 1.1 to 15.9 years (AOR = 0.59; 95% CI, 0.45-0.79); were ages 16 to 65 years (AOR = 0.79; 95% CI, 0.63-0.99); or had a body mass index < 25 (AOR = 0.82; 95% CI, 0.71-0.95).

Higher D levels are a different story. Vitamin D supplementation in people with circulating levels of 25-hydroxyvitamin D ≥ 30 ng/mL did not appear to provide benefit (AOR = 0.96; 95% CI, 0.78-1.18). Supplementation in this population did not influence any of the secondary outcomes, including risk for all-cause serious adverse events (AOR = 0.98; 95% CI, 0.80-1.20).

WHAT’S NEW

A more accurate snapshot

Previous studies of vitamin D and respiratory tract infections were mostly observational in nature. Those that were RCTs used variable doses of vitamin D, had variable baseline 25-hydroxyvitamin D levels, and employed various methods to monitor ARTI symptoms/incidence.^5-8 This is the first systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials with supplementation using vitamin D₃ or vitamin D₂ that used individual participant-level data, which gives a more accurate estimate of outcomes when compared with traditional meta-analyses.

CAVEATS

Only the most deficient benefit?

Vitamin D supplementation was safe and protected against ARTIs overall, but the greatest effect of vitamin D supplementation on the prevention of ARTIs was noted in those who were most severely vitamin D deficient (those with circulating 25-hydroxyvitamin levels < 10 ng/mL, NNT = 4; 10-28 ng/mL, NNT = 15). There was no demonstrable effect once circulating 25-hydroxyvitamin D levels reached 30 ng/mL.

CHALLENGES TO IMPLEMENTATION

Breaking tradition

The study found that both daily and weekly doses of vitamin D were effective in reducing the incidence of ARTIs, but the doses used were much lower than the commonly used 10,000 to 50,000 IU bolus doses, which were ineffective in reducing ARTIs in the current meta-analysis. Since bolus dosing is an ingrained practice for many providers, changing this may prove challenging.

Continue to: In addition...

In addition, the authors of the study suggest that one of the ways to provide this level of vitamin D is through food fortification, but food fortification is often complicated by emotional and/or political issues that could thwart implementation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

CASE

A 38-year-old man presents to your primary care clinic with chronic low back stiffness and pain. You have evaluated and treated this patient for this complaint for more than a year. His symptoms are worse in the morning upon wakening and improve with activity and anti-inflammatory medications. He denies any trauma or change in his activity level. His medical history includes chronic insertional Achilles pain and plantar fasciopathy, both for approximately 2 years. The patient reports no systemic or constitutional symptoms, and no pertinent family history.

How would you proceed with his work-up?

Ankylosing spondylitis (AS) is a form of arthritis that primarily affects the spine and sacroiliac joints. It is the most common spondyloarthropathy (SpA)—a family of disorders that also includes psoriatic arthritis; arthritis associated with inflammatory bowel disease; reactive arthritis; and juvenile SpA.¹ AS is most prevalent in Caucasians and may affect 0.1% to 1.4% of the population.²

Historically, a diagnosis of AS required radiographic evidence of inflammation of the axial spine or sacrum that manifested as chronic stiffness and back pain. However, the disease can also be mild or take time for radiographic evidence to appear. So an umbrella term emerged—axial spondyloarthritis (axSpA)—that includes both AS and the less severe form, called nonradiographic axSpA (nr-axSpA). While patients with AS exhibit radiographic abnormalities consistent with sacroiliitis, patients with early, or nr-axSpA, do not have radiographic abnormalities of the sacroiliac (SI) joint or axial spine.

In clinical practice, the distinction between AS and nr-axSpA has limited impact on the management of individual patients. However, early recognition, intervention, and treatment in patients who do not meet radiographic criteria for AS can improve patient-oriented outcomes.

The family physician (FP)’s role. It is not necessary that FPs be able to make a definitive diagnosis, but FPs should:

• be able to recognize the symptoms of inflammatory back pain (IBP);
• know which radiographic and laboratory studies to obtain and when;
• know the Assessment of SpondyloArthritis international Society (ASAS) criteria³ that assist in identifying patients at risk for axSpA; and
• know when to refer moderate- to high-risk patients to rheumatologists for assistance with the diagnosis.

FPs should have a high index of suspicion in any patient who has chronic back pain (> 3 months) with other features of SpA, and should pay special attention to young adult patients (< 45 years) who have IBP features.

Continue to: Definitive data to show...

Definitive data to show what percentage of patients with nr-axSpA progress to AS are lacking. However, early identification of AS is important, as those who go undiagnosed have increased back pain, stiffness, progressive loss of mobility, and decreased quality of life. In addition, patients diagnosed after significant sacroiliitis is visible are less responsive to treatment.⁴

It takes an average of 5 to 7 years for patients with radiographic evidence of ankylosing spondylitis to receive the proper diagnosis.

What follows is a review of what you’ll see and the tools that will help with diagnosis and referral.

The diagnosis dilemma

In the past, the modified New York criteria have been used to define AS, but they require the presence of both clinical symptoms and radiographic findings indicative of sacroiliitis for an AS designation.^5,6 Because radiographic sacroiliitis can be a late finding in axSpA and nonexistent in nr-asSpA, these criteria are of limited clinical utility.

To assist in early identification, the ASAS published criteria to classify patients with early axSpA prior to radiographic manifestations.³ While not strictly diagnostic, these criteria combine patient history that includes evidence of IBP, human leukocyte antigen (HLA)-B27 positivity, and radiography to assist health care providers in identifying patients who may have axSpA and need prompt referral to a rheumatologist.

Easy to miss, even with evidence. It takes an average of 5 to 7 years for patients with radiographic evidence of AS to receive the proper diagnosis.⁷ There are several reasons for this. First, the axSpA spectrum encompasses a small percentage of patients who present to health care providers with back pain. In addition, many providers overlook the signs and symptoms of IBP, which are a hallmark of the condition. And finally, as stated earlier, true criteria for the diagnosis of axSpA do not exist.

Continue to: In addition...

In addition, AS predominantly affects people in the third and fourth decades of life, but as many as 5% of patients of all ages with chronic back pain (> 3 months) can be classified as having AS.⁸ In patients who have IBP features, 14% can be classified as having axSpA.⁹ Therefore, it is important to recognize the features of IBP (TABLE 1¹⁰). The presence of 4 of the 5 of IBP features has a sensitivity of 77% and a specificity of 91.7% for IBP.¹⁰

A different kind of back pain. The vast majority of patients presenting with low back pain will have features of mechanical back pain, which include improvement with rest, mild and short-lived morning stiffness and/or pain upon waking, and the absence of inflammatory markers. Those with axSpA, on the other hand, are more likely to report improvement of pain with exercise, no improvement with rest, and pain at night with improvement upon rising. While the presence of IBP features alone isn’t diagnostic for nr-axSpA or AS, such features should increase your suspicion, especially when such features are present in younger patients.

Physical exam findings

Physical exam findings are neither sensitive nor specific for the diagnosis of an axSpA disorder, but can help build a case for one. The physical exam can also assist in identifying comorbid conditions including uveitis, psoriasis, dactylitis, and enthesitis. Experts do not recommend using serial measurements of axial range of motion because they are time-consuming, and normative values are highly variable.

On examination of the peripheral joints and feet, note any swollen, tender, or deformed joints, as well as any dactylitis. Although any enthesis can be affected in axSpA, the insertional points of the Achilles and the plantar fascia are the most typical,¹ so pay particular attention to these areas. On skin exam, note any evidence of psoriatic manifestations. Refer all patients with suspected uveitis to an ophthalmologist for confirmation of the diagnosis.

Lab studies: Not definitive, but helpful

No laboratory studies confirm a diagnosis of nr-axSpA or AS; however, 2 studies—C-reactive protein (CRP) and HLA-B27—are important, as levels are listed as part of ASAS’s axSpA features (TABLE 2³) and are factors that should be considered when deciding whether a referral is needed (TABLE 3¹¹). As such, HLA-B27 and CRP testing should be performed in all patients suspected of having an axSpA spectrum disorder.

Continue to: HLA-B27 is...

HLA-B27 is positive in 70% to 95% of patients with axSpA and can help build a case for the disorder.^6,12 CRP is useful too, as an elevated CRP has important treatment implications (more on that in a bit).⁶

Other diagnoses in the differential include: degenerative disc disease, lumbar spondylosis, congenital vertebral anomalies, and osteoarthritis of the SI joint, bone metastasis, or primary bone tumors.¹

Start with plain x-rays. The American College of Radiology (ACR) published appropriateness criteria for obtaining x-rays in patients suspected of having axSpA.¹³ Plain x-rays of the spine and SI joint are recommended for the initial evaluation. Magnetic resonance imaging (MRI) of the SI joint and/or spine should be obtained if the initial x-rays are negative or equivocal. Patient symptomology and/or exam findings determine whether to include the SI joint and/or spine. If the patient has subjective and objective findings concerning for pathology of both, then an MRI of the spine and SI joint is warranted.

HLA-B27 is positive in 70%-95% of patients with axSpA.

Alternatively, computed tomography (CT) can be substituted if MRI is unavailable. In patients with known axSpA, surveillance radiography should not occur more often than every 2 years.⁶

Timely referral is essential

Timely referral to a rheumatologist is an essential part of early diagnosis and treatment. Advances in treatment options for axSpA have become available in recent years and offer new hope for patients.

Continue to: As the presence of IBP...

As the presence of IBP features portends a 3-fold increase in the risk for axSpA,⁸ we propose an approach to the referral of patients with IBP features that deviates slightly from the ASAS algorithm. We believe it is within the scope of FPs to recognize IBP features, order appropriate ancillary studies, start a trial of nonsteroidal anti-inflammatory drugs (NSAIDs), and follow-up with patients in 2 to 4 weeks to review results and evaluate treatment response. As such, all patients < 45 years old with IBP symptoms (TABLE 1¹⁰) for 3 months or longer should be sent for laboratory workup (HLA-B27, CRP) and plain radiographs of the sacroiliac joints and lumbar spine.

The only modifiable predictor of progression to axSpA is smoking.

Older patients, patients with IBP features for < 3 months, or patients < 45 years with IBP that have negative lab testing and negative radiographs should start an exercise program, be treated with an NSAID, and be assessed for ASAS spondyloarthritis features (TABLE 2³).

Any patient with positive lab testing, positive radiographs, or ≥ 1 ASAS axSpA features should be referred to Rheumatology (TABLE 3¹¹). Patients with a negative radiograph should be evaluated with an MRI of the SI joints or spine (driven by pain location) and referred to Rheumatology if positive.

Keep in mind that not all patients fit neatly into an algorithm or a classification system. Therefore, we recommend that any patient with IBP features who fails to improve after 3 months of an exercise program, for whom you have a high index of suspicion for possible axSpA spectrum disease, receive appropriate ancillary studies and referral for expert consultation.

Exercise and NSAIDs form the basis of treatment

The purpose of treating patients with a suspected axSpA spectrum disorder is to decrease pain and stiffness, improve function and quality of life, and, ideally, halt or slow progression of disease. The only modifiable predictor of progression to axSpA is smoking; as such, encourage tobacco cessation if appropriate.¹⁴

Continue to: Nonpharmacologic treatment...

Nonpharmacologic treatment, such as regular aerobic exercise and strength training, should be prescribed for all patients with axSpA.⁶ Regular exercise is helpful in improving lower back pain, function, and spinal mobility. Combination endurance and strength-training programs are associated with the greatest benefits, and aquatic therapy is better than land-based therapy for pain.¹⁵ That said, recommend land-based exercises over no exercise when pool-based therapy is unavailable.

NSAIDs (eg, ibuprofen 200-800 mg at variable frequency, up to a maximum dose of 2400 mg/d; naproxen 250-500 mg bid) are the core treatment for patients with axSpA, as they improve pain, function, and quality of life.⁶ Both traditional NSAIDs and cyclooxygenase II (COX-II) inhibitors are effective; no differences in efficacy exist between the classes.^6,15,16

Prompt diagnosis of patients with ankylosing spondylitis is important because those diagnosed after significant sacroiliitis is visible are less responsive to treatment.

NSAIDs have been shown to be as safe as placebo for up to 12 weeks of continuous use in patients without gastritis or renal disease.¹⁶ In patients with a gastrointestinal comorbidity, use NSAIDs cautiously.¹⁷

If adequate pain relief is not obtained after 2 to 4 weeks of NSAID use, try a different NSAID prior to escalating treatment.⁶ More research is needed to evaluate the effect of NSAIDs on spinal radiographic progression of disease because of conflicting results of existing studies.¹⁶

Unlike with other rheumatologic disorders, oral glucocorticoids and traditional disease-modifying anti-rheumatic drugs (DMARDs) are not effective in axSpA and should not be prescribed.¹⁸

Continue to: Other agents

Other agents. In patients who continue to have symptoms, or cannot tolerate 12 weeks of NSAIDs, newer biologic DMARDs may be considered. Tumor necrosis factor inhibitors (TNFi) and interleukin-17 inhibitors (IL-17i) have shown the best efficacy.^18,19 In patients with AS, these medications improve pain and function, increase the chance of achieving partial remission of symptoms, and reduce CRP levels and MRI-detectable inflammation of the SI joint and/or spine.^1,19 At this time, these medications are reserved for use in patients with clinical symptoms consistent with, and radiographic evidence of, axSpA, or in patients with nr-axSpA who have elevated CRP levels.¹⁸

For patients diagnosed with axSpA, an elevated CRP, short symptom duration (or young age), and inflammation noted on MRI seem to be the best predictors of a good response to TNFi.²⁰ All patients in whom biologic DMARDS are considered should be referred to a rheumatologist because of cost, potential adverse effects, and stringent indications for use.

Surveil disease progression to prevent complications

We don’t yet know if progression of axSpA is linear or if the process can be slowed or halted with timely treatment. We do know that the natural history of structural progression is low in patients with early nr-axSpA.

Examples of validated online tools that can assist in measuring patient response to treatment and/or progression of disease follow.²¹ They can be used alone or in combination to help monitor treatment and progression of disease.

• The Ankylosing Spondylitis Disease Activity Score (ASDAS) (https://www.asas-group.org/clinical-instruments/asdas-calculator/). This measure of disease activity uses a 5-item patient assessment and CRP level measurement.
• The Bath Ankylosing Spondylitis Functional Index (BASFI) (http://basdai.com/BASFI.php). The BASFI consists of 8 items pertaining to everyday function and 2 items assessing the ability of patients to cope with everyday life.
• The Ankylosing Spondylitis Quality of Life Scale (ASQoL; http://oml.eular.org/sysModules/obxOml/docs/ID_32/ASQoL%20Questionnaire%20English.pdf).The ASQoL is an 18-item questionnaire related to the impact of disease on sleep, mood, motivation, and activities of daily living, among others.

Comorbidities. Patients with axSpA have an increased lifetime risk for cardiovascular disease, osteoporosis, fracture, inflammatory bowel disease, and iritis.⁶ Acute back pain in a patient with axSpA should be evaluated for a fracture and not automatically deemed an axSpA flare.¹³ Obtain a CT scan of the spine for all patients with known spine ankyloses who are suspected of having a fracture (because of the low sensitivity of plain radiography).¹³

Continue to: Prognosis

Prognosis. AS is a progressive long-term medical condition. Patients may experience progressive spinal deformity, hip joint or sacroiliac arthroses, or neurologic compromise after trauma. Reserve surgical referral for patients with spinal deformity that significantly affects quality of life and is severe or progressing despite nonpharmacologic and pharmacologic measures. Refer patients with an unstable spinal fracture for surgical intervention.⁶

Order HLA-B27 and C-reactive protein testing in all patients suspected of having an axial spondyloarthritis spectrum disorder.

Advise patients of available local, national, and international support groups. The National Ankylosis Spondylitis Society (NASS) based in the United Kingdom and the Spondylitis Association of America (SAA) are patient-friendly, nonprofit organizations that provide resources and information to people to help them learn about and cope with their condition.

CASE

You diagnose IBP in this patient and proceed with a work-up. You order x-rays of the back and SI joint, a CRP level, and an HLA-B27 test. X-rays and laboratory studies are negative. The patient is encouraged by your recommendation to start an aerobic and strength training home exercise program. In addition, you prescribe naproxen 500 mg bid and ask the patient to return in 1 month.

On follow-up he states that the naproxen is working well to control his pain. Upon further chart review and questioning, the patient confirms a history of chronic plantar fasciosis and psoriasis that he has controlled with intermittent topical steroids. He denies visual disturbances or gastrointestinal complaints. You refer him to a rheumatologist, where biologic agents are discussed but not prescribed at this time.

CORRESPONDENCE
Carlton J Covey, MD, FAAFP, Nellis Family Medicine Residency Program, 4700 Las Vegas Blvd. North, Nellis AFB, NV 89191; [email protected]

CASE

A 38-year-old man presents to your primary care clinic with chronic low back stiffness and pain. You have evaluated and treated this patient for this complaint for more than a year. His symptoms are worse in the morning upon wakening and improve with activity and anti-inflammatory medications. He denies any trauma or change in his activity level. His medical history includes chronic insertional Achilles pain and plantar fasciopathy, both for approximately 2 years. The patient reports no systemic or constitutional symptoms, and no pertinent family history.

How would you proceed with his work-up?

Ankylosing spondylitis (AS) is a form of arthritis that primarily affects the spine and sacroiliac joints. It is the most common spondyloarthropathy (SpA)—a family of disorders that also includes psoriatic arthritis; arthritis associated with inflammatory bowel disease; reactive arthritis; and juvenile SpA.¹ AS is most prevalent in Caucasians and may affect 0.1% to 1.4% of the population.²

Historically, a diagnosis of AS required radiographic evidence of inflammation of the axial spine or sacrum that manifested as chronic stiffness and back pain. However, the disease can also be mild or take time for radiographic evidence to appear. So an umbrella term emerged—axial spondyloarthritis (axSpA)—that includes both AS and the less severe form, called nonradiographic axSpA (nr-axSpA). While patients with AS exhibit radiographic abnormalities consistent with sacroiliitis, patients with early, or nr-axSpA, do not have radiographic abnormalities of the sacroiliac (SI) joint or axial spine.

In clinical practice, the distinction between AS and nr-axSpA has limited impact on the management of individual patients. However, early recognition, intervention, and treatment in patients who do not meet radiographic criteria for AS can improve patient-oriented outcomes.

The family physician (FP)’s role. It is not necessary that FPs be able to make a definitive diagnosis, but FPs should:

• be able to recognize the symptoms of inflammatory back pain (IBP);
• know which radiographic and laboratory studies to obtain and when;
• know the Assessment of SpondyloArthritis international Society (ASAS) criteria³ that assist in identifying patients at risk for axSpA; and
• know when to refer moderate- to high-risk patients to rheumatologists for assistance with the diagnosis.

FPs should have a high index of suspicion in any patient who has chronic back pain (> 3 months) with other features of SpA, and should pay special attention to young adult patients (< 45 years) who have IBP features.

Continue to: Definitive data to show...

Definitive data to show what percentage of patients with nr-axSpA progress to AS are lacking. However, early identification of AS is important, as those who go undiagnosed have increased back pain, stiffness, progressive loss of mobility, and decreased quality of life. In addition, patients diagnosed after significant sacroiliitis is visible are less responsive to treatment.⁴

It takes an average of 5 to 7 years for patients with radiographic evidence of ankylosing spondylitis to receive the proper diagnosis.

What follows is a review of what you’ll see and the tools that will help with diagnosis and referral.

The diagnosis dilemma

In the past, the modified New York criteria have been used to define AS, but they require the presence of both clinical symptoms and radiographic findings indicative of sacroiliitis for an AS designation.^5,6 Because radiographic sacroiliitis can be a late finding in axSpA and nonexistent in nr-asSpA, these criteria are of limited clinical utility.

To assist in early identification, the ASAS published criteria to classify patients with early axSpA prior to radiographic manifestations.³ While not strictly diagnostic, these criteria combine patient history that includes evidence of IBP, human leukocyte antigen (HLA)-B27 positivity, and radiography to assist health care providers in identifying patients who may have axSpA and need prompt referral to a rheumatologist.

Easy to miss, even with evidence. It takes an average of 5 to 7 years for patients with radiographic evidence of AS to receive the proper diagnosis.⁷ There are several reasons for this. First, the axSpA spectrum encompasses a small percentage of patients who present to health care providers with back pain. In addition, many providers overlook the signs and symptoms of IBP, which are a hallmark of the condition. And finally, as stated earlier, true criteria for the diagnosis of axSpA do not exist.

Continue to: In addition...

In addition, AS predominantly affects people in the third and fourth decades of life, but as many as 5% of patients of all ages with chronic back pain (> 3 months) can be classified as having AS.⁸ In patients who have IBP features, 14% can be classified as having axSpA.⁹ Therefore, it is important to recognize the features of IBP (TABLE 1¹⁰). The presence of 4 of the 5 of IBP features has a sensitivity of 77% and a specificity of 91.7% for IBP.¹⁰

A different kind of back pain. The vast majority of patients presenting with low back pain will have features of mechanical back pain, which include improvement with rest, mild and short-lived morning stiffness and/or pain upon waking, and the absence of inflammatory markers. Those with axSpA, on the other hand, are more likely to report improvement of pain with exercise, no improvement with rest, and pain at night with improvement upon rising. While the presence of IBP features alone isn’t diagnostic for nr-axSpA or AS, such features should increase your suspicion, especially when such features are present in younger patients.

Physical exam findings

Physical exam findings are neither sensitive nor specific for the diagnosis of an axSpA disorder, but can help build a case for one. The physical exam can also assist in identifying comorbid conditions including uveitis, psoriasis, dactylitis, and enthesitis. Experts do not recommend using serial measurements of axial range of motion because they are time-consuming, and normative values are highly variable.

On examination of the peripheral joints and feet, note any swollen, tender, or deformed joints, as well as any dactylitis. Although any enthesis can be affected in axSpA, the insertional points of the Achilles and the plantar fascia are the most typical,¹ so pay particular attention to these areas. On skin exam, note any evidence of psoriatic manifestations. Refer all patients with suspected uveitis to an ophthalmologist for confirmation of the diagnosis.

Lab studies: Not definitive, but helpful

No laboratory studies confirm a diagnosis of nr-axSpA or AS; however, 2 studies—C-reactive protein (CRP) and HLA-B27—are important, as levels are listed as part of ASAS’s axSpA features (TABLE 2³) and are factors that should be considered when deciding whether a referral is needed (TABLE 3¹¹). As such, HLA-B27 and CRP testing should be performed in all patients suspected of having an axSpA spectrum disorder.

Continue to: HLA-B27 is...

HLA-B27 is positive in 70% to 95% of patients with axSpA and can help build a case for the disorder.^6,12 CRP is useful too, as an elevated CRP has important treatment implications (more on that in a bit).⁶

Other diagnoses in the differential include: degenerative disc disease, lumbar spondylosis, congenital vertebral anomalies, and osteoarthritis of the SI joint, bone metastasis, or primary bone tumors.¹

Start with plain x-rays. The American College of Radiology (ACR) published appropriateness criteria for obtaining x-rays in patients suspected of having axSpA.¹³ Plain x-rays of the spine and SI joint are recommended for the initial evaluation. Magnetic resonance imaging (MRI) of the SI joint and/or spine should be obtained if the initial x-rays are negative or equivocal. Patient symptomology and/or exam findings determine whether to include the SI joint and/or spine. If the patient has subjective and objective findings concerning for pathology of both, then an MRI of the spine and SI joint is warranted.

HLA-B27 is positive in 70%-95% of patients with axSpA.

Alternatively, computed tomography (CT) can be substituted if MRI is unavailable. In patients with known axSpA, surveillance radiography should not occur more often than every 2 years.⁶

Timely referral is essential

Timely referral to a rheumatologist is an essential part of early diagnosis and treatment. Advances in treatment options for axSpA have become available in recent years and offer new hope for patients.

Continue to: As the presence of IBP...

As the presence of IBP features portends a 3-fold increase in the risk for axSpA,⁸ we propose an approach to the referral of patients with IBP features that deviates slightly from the ASAS algorithm. We believe it is within the scope of FPs to recognize IBP features, order appropriate ancillary studies, start a trial of nonsteroidal anti-inflammatory drugs (NSAIDs), and follow-up with patients in 2 to 4 weeks to review results and evaluate treatment response. As such, all patients < 45 years old with IBP symptoms (TABLE 1¹⁰) for 3 months or longer should be sent for laboratory workup (HLA-B27, CRP) and plain radiographs of the sacroiliac joints and lumbar spine.

The only modifiable predictor of progression to axSpA is smoking.

Older patients, patients with IBP features for < 3 months, or patients < 45 years with IBP that have negative lab testing and negative radiographs should start an exercise program, be treated with an NSAID, and be assessed for ASAS spondyloarthritis features (TABLE 2³).

Any patient with positive lab testing, positive radiographs, or ≥ 1 ASAS axSpA features should be referred to Rheumatology (TABLE 3¹¹). Patients with a negative radiograph should be evaluated with an MRI of the SI joints or spine (driven by pain location) and referred to Rheumatology if positive.

Keep in mind that not all patients fit neatly into an algorithm or a classification system. Therefore, we recommend that any patient with IBP features who fails to improve after 3 months of an exercise program, for whom you have a high index of suspicion for possible axSpA spectrum disease, receive appropriate ancillary studies and referral for expert consultation.

Exercise and NSAIDs form the basis of treatment

The purpose of treating patients with a suspected axSpA spectrum disorder is to decrease pain and stiffness, improve function and quality of life, and, ideally, halt or slow progression of disease. The only modifiable predictor of progression to axSpA is smoking; as such, encourage tobacco cessation if appropriate.¹⁴

Continue to: Nonpharmacologic treatment...

Nonpharmacologic treatment, such as regular aerobic exercise and strength training, should be prescribed for all patients with axSpA.⁶ Regular exercise is helpful in improving lower back pain, function, and spinal mobility. Combination endurance and strength-training programs are associated with the greatest benefits, and aquatic therapy is better than land-based therapy for pain.¹⁵ That said, recommend land-based exercises over no exercise when pool-based therapy is unavailable.

NSAIDs (eg, ibuprofen 200-800 mg at variable frequency, up to a maximum dose of 2400 mg/d; naproxen 250-500 mg bid) are the core treatment for patients with axSpA, as they improve pain, function, and quality of life.⁶ Both traditional NSAIDs and cyclooxygenase II (COX-II) inhibitors are effective; no differences in efficacy exist between the classes.^6,15,16

Prompt diagnosis of patients with ankylosing spondylitis is important because those diagnosed after significant sacroiliitis is visible are less responsive to treatment.

NSAIDs have been shown to be as safe as placebo for up to 12 weeks of continuous use in patients without gastritis or renal disease.¹⁶ In patients with a gastrointestinal comorbidity, use NSAIDs cautiously.¹⁷

If adequate pain relief is not obtained after 2 to 4 weeks of NSAID use, try a different NSAID prior to escalating treatment.⁶ More research is needed to evaluate the effect of NSAIDs on spinal radiographic progression of disease because of conflicting results of existing studies.¹⁶

Unlike with other rheumatologic disorders, oral glucocorticoids and traditional disease-modifying anti-rheumatic drugs (DMARDs) are not effective in axSpA and should not be prescribed.¹⁸

Continue to: Other agents

Other agents. In patients who continue to have symptoms, or cannot tolerate 12 weeks of NSAIDs, newer biologic DMARDs may be considered. Tumor necrosis factor inhibitors (TNFi) and interleukin-17 inhibitors (IL-17i) have shown the best efficacy.^18,19 In patients with AS, these medications improve pain and function, increase the chance of achieving partial remission of symptoms, and reduce CRP levels and MRI-detectable inflammation of the SI joint and/or spine.^1,19 At this time, these medications are reserved for use in patients with clinical symptoms consistent with, and radiographic evidence of, axSpA, or in patients with nr-axSpA who have elevated CRP levels.¹⁸

For patients diagnosed with axSpA, an elevated CRP, short symptom duration (or young age), and inflammation noted on MRI seem to be the best predictors of a good response to TNFi.²⁰ All patients in whom biologic DMARDS are considered should be referred to a rheumatologist because of cost, potential adverse effects, and stringent indications for use.

Surveil disease progression to prevent complications

We don’t yet know if progression of axSpA is linear or if the process can be slowed or halted with timely treatment. We do know that the natural history of structural progression is low in patients with early nr-axSpA.

Examples of validated online tools that can assist in measuring patient response to treatment and/or progression of disease follow.²¹ They can be used alone or in combination to help monitor treatment and progression of disease.

• The Ankylosing Spondylitis Disease Activity Score (ASDAS) (https://www.asas-group.org/clinical-instruments/asdas-calculator/). This measure of disease activity uses a 5-item patient assessment and CRP level measurement.
• The Bath Ankylosing Spondylitis Functional Index (BASFI) (http://basdai.com/BASFI.php). The BASFI consists of 8 items pertaining to everyday function and 2 items assessing the ability of patients to cope with everyday life.
• The Ankylosing Spondylitis Quality of Life Scale (ASQoL; http://oml.eular.org/sysModules/obxOml/docs/ID_32/ASQoL%20Questionnaire%20English.pdf).The ASQoL is an 18-item questionnaire related to the impact of disease on sleep, mood, motivation, and activities of daily living, among others.

Comorbidities. Patients with axSpA have an increased lifetime risk for cardiovascular disease, osteoporosis, fracture, inflammatory bowel disease, and iritis.⁶ Acute back pain in a patient with axSpA should be evaluated for a fracture and not automatically deemed an axSpA flare.¹³ Obtain a CT scan of the spine for all patients with known spine ankyloses who are suspected of having a fracture (because of the low sensitivity of plain radiography).¹³

Continue to: Prognosis

Prognosis. AS is a progressive long-term medical condition. Patients may experience progressive spinal deformity, hip joint or sacroiliac arthroses, or neurologic compromise after trauma. Reserve surgical referral for patients with spinal deformity that significantly affects quality of life and is severe or progressing despite nonpharmacologic and pharmacologic measures. Refer patients with an unstable spinal fracture for surgical intervention.⁶

Order HLA-B27 and C-reactive protein testing in all patients suspected of having an axial spondyloarthritis spectrum disorder.

Advise patients of available local, national, and international support groups. The National Ankylosis Spondylitis Society (NASS) based in the United Kingdom and the Spondylitis Association of America (SAA) are patient-friendly, nonprofit organizations that provide resources and information to people to help them learn about and cope with their condition.

CASE

You diagnose IBP in this patient and proceed with a work-up. You order x-rays of the back and SI joint, a CRP level, and an HLA-B27 test. X-rays and laboratory studies are negative. The patient is encouraged by your recommendation to start an aerobic and strength training home exercise program. In addition, you prescribe naproxen 500 mg bid and ask the patient to return in 1 month.

On follow-up he states that the naproxen is working well to control his pain. Upon further chart review and questioning, the patient confirms a history of chronic plantar fasciosis and psoriasis that he has controlled with intermittent topical steroids. He denies visual disturbances or gastrointestinal complaints. You refer him to a rheumatologist, where biologic agents are discussed but not prescribed at this time.

CORRESPONDENCE
Carlton J Covey, MD, FAAFP, Nellis Family Medicine Residency Program, 4700 Las Vegas Blvd. North, Nellis AFB, NV 89191; [email protected]

CASE

A 38-year-old man presents to your primary care clinic with chronic low back stiffness and pain. You have evaluated and treated this patient for this complaint for more than a year. His symptoms are worse in the morning upon wakening and improve with activity and anti-inflammatory medications. He denies any trauma or change in his activity level. His medical history includes chronic insertional Achilles pain and plantar fasciopathy, both for approximately 2 years. The patient reports no systemic or constitutional symptoms, and no pertinent family history.

How would you proceed with his work-up?

Ankylosing spondylitis (AS) is a form of arthritis that primarily affects the spine and sacroiliac joints. It is the most common spondyloarthropathy (SpA)—a family of disorders that also includes psoriatic arthritis; arthritis associated with inflammatory bowel disease; reactive arthritis; and juvenile SpA.¹ AS is most prevalent in Caucasians and may affect 0.1% to 1.4% of the population.²

Historically, a diagnosis of AS required radiographic evidence of inflammation of the axial spine or sacrum that manifested as chronic stiffness and back pain. However, the disease can also be mild or take time for radiographic evidence to appear. So an umbrella term emerged—axial spondyloarthritis (axSpA)—that includes both AS and the less severe form, called nonradiographic axSpA (nr-axSpA). While patients with AS exhibit radiographic abnormalities consistent with sacroiliitis, patients with early, or nr-axSpA, do not have radiographic abnormalities of the sacroiliac (SI) joint or axial spine.

In clinical practice, the distinction between AS and nr-axSpA has limited impact on the management of individual patients. However, early recognition, intervention, and treatment in patients who do not meet radiographic criteria for AS can improve patient-oriented outcomes.

The family physician (FP)’s role. It is not necessary that FPs be able to make a definitive diagnosis, but FPs should:

• be able to recognize the symptoms of inflammatory back pain (IBP);
• know which radiographic and laboratory studies to obtain and when;
• know the Assessment of SpondyloArthritis international Society (ASAS) criteria³ that assist in identifying patients at risk for axSpA; and
• know when to refer moderate- to high-risk patients to rheumatologists for assistance with the diagnosis.

FPs should have a high index of suspicion in any patient who has chronic back pain (> 3 months) with other features of SpA, and should pay special attention to young adult patients (< 45 years) who have IBP features.

Continue to: Definitive data to show...

Definitive data to show what percentage of patients with nr-axSpA progress to AS are lacking. However, early identification of AS is important, as those who go undiagnosed have increased back pain, stiffness, progressive loss of mobility, and decreased quality of life. In addition, patients diagnosed after significant sacroiliitis is visible are less responsive to treatment.⁴

It takes an average of 5 to 7 years for patients with radiographic evidence of ankylosing spondylitis to receive the proper diagnosis.

What follows is a review of what you’ll see and the tools that will help with diagnosis and referral.

The diagnosis dilemma

In the past, the modified New York criteria have been used to define AS, but they require the presence of both clinical symptoms and radiographic findings indicative of sacroiliitis for an AS designation.^5,6 Because radiographic sacroiliitis can be a late finding in axSpA and nonexistent in nr-asSpA, these criteria are of limited clinical utility.

To assist in early identification, the ASAS published criteria to classify patients with early axSpA prior to radiographic manifestations.³ While not strictly diagnostic, these criteria combine patient history that includes evidence of IBP, human leukocyte antigen (HLA)-B27 positivity, and radiography to assist health care providers in identifying patients who may have axSpA and need prompt referral to a rheumatologist.

Easy to miss, even with evidence. It takes an average of 5 to 7 years for patients with radiographic evidence of AS to receive the proper diagnosis.⁷ There are several reasons for this. First, the axSpA spectrum encompasses a small percentage of patients who present to health care providers with back pain. In addition, many providers overlook the signs and symptoms of IBP, which are a hallmark of the condition. And finally, as stated earlier, true criteria for the diagnosis of axSpA do not exist.

Continue to: In addition...

In addition, AS predominantly affects people in the third and fourth decades of life, but as many as 5% of patients of all ages with chronic back pain (> 3 months) can be classified as having AS.⁸ In patients who have IBP features, 14% can be classified as having axSpA.⁹ Therefore, it is important to recognize the features of IBP (TABLE 1¹⁰). The presence of 4 of the 5 of IBP features has a sensitivity of 77% and a specificity of 91.7% for IBP.¹⁰

A different kind of back pain. The vast majority of patients presenting with low back pain will have features of mechanical back pain, which include improvement with rest, mild and short-lived morning stiffness and/or pain upon waking, and the absence of inflammatory markers. Those with axSpA, on the other hand, are more likely to report improvement of pain with exercise, no improvement with rest, and pain at night with improvement upon rising. While the presence of IBP features alone isn’t diagnostic for nr-axSpA or AS, such features should increase your suspicion, especially when such features are present in younger patients.

Physical exam findings

Physical exam findings are neither sensitive nor specific for the diagnosis of an axSpA disorder, but can help build a case for one. The physical exam can also assist in identifying comorbid conditions including uveitis, psoriasis, dactylitis, and enthesitis. Experts do not recommend using serial measurements of axial range of motion because they are time-consuming, and normative values are highly variable.

On examination of the peripheral joints and feet, note any swollen, tender, or deformed joints, as well as any dactylitis. Although any enthesis can be affected in axSpA, the insertional points of the Achilles and the plantar fascia are the most typical,¹ so pay particular attention to these areas. On skin exam, note any evidence of psoriatic manifestations. Refer all patients with suspected uveitis to an ophthalmologist for confirmation of the diagnosis.

Lab studies: Not definitive, but helpful

No laboratory studies confirm a diagnosis of nr-axSpA or AS; however, 2 studies—C-reactive protein (CRP) and HLA-B27—are important, as levels are listed as part of ASAS’s axSpA features (TABLE 2³) and are factors that should be considered when deciding whether a referral is needed (TABLE 3¹¹). As such, HLA-B27 and CRP testing should be performed in all patients suspected of having an axSpA spectrum disorder.

Continue to: HLA-B27 is...

HLA-B27 is positive in 70% to 95% of patients with axSpA and can help build a case for the disorder.^6,12 CRP is useful too, as an elevated CRP has important treatment implications (more on that in a bit).⁶

Other diagnoses in the differential include: degenerative disc disease, lumbar spondylosis, congenital vertebral anomalies, and osteoarthritis of the SI joint, bone metastasis, or primary bone tumors.¹

Start with plain x-rays. The American College of Radiology (ACR) published appropriateness criteria for obtaining x-rays in patients suspected of having axSpA.¹³ Plain x-rays of the spine and SI joint are recommended for the initial evaluation. Magnetic resonance imaging (MRI) of the SI joint and/or spine should be obtained if the initial x-rays are negative or equivocal. Patient symptomology and/or exam findings determine whether to include the SI joint and/or spine. If the patient has subjective and objective findings concerning for pathology of both, then an MRI of the spine and SI joint is warranted.

HLA-B27 is positive in 70%-95% of patients with axSpA.

Alternatively, computed tomography (CT) can be substituted if MRI is unavailable. In patients with known axSpA, surveillance radiography should not occur more often than every 2 years.⁶

Timely referral is essential

Timely referral to a rheumatologist is an essential part of early diagnosis and treatment. Advances in treatment options for axSpA have become available in recent years and offer new hope for patients.

Continue to: As the presence of IBP...

As the presence of IBP features portends a 3-fold increase in the risk for axSpA,⁸ we propose an approach to the referral of patients with IBP features that deviates slightly from the ASAS algorithm. We believe it is within the scope of FPs to recognize IBP features, order appropriate ancillary studies, start a trial of nonsteroidal anti-inflammatory drugs (NSAIDs), and follow-up with patients in 2 to 4 weeks to review results and evaluate treatment response. As such, all patients < 45 years old with IBP symptoms (TABLE 1¹⁰) for 3 months or longer should be sent for laboratory workup (HLA-B27, CRP) and plain radiographs of the sacroiliac joints and lumbar spine.

The only modifiable predictor of progression to axSpA is smoking.

Older patients, patients with IBP features for < 3 months, or patients < 45 years with IBP that have negative lab testing and negative radiographs should start an exercise program, be treated with an NSAID, and be assessed for ASAS spondyloarthritis features (TABLE 2³).

Any patient with positive lab testing, positive radiographs, or ≥ 1 ASAS axSpA features should be referred to Rheumatology (TABLE 3¹¹). Patients with a negative radiograph should be evaluated with an MRI of the SI joints or spine (driven by pain location) and referred to Rheumatology if positive.

Keep in mind that not all patients fit neatly into an algorithm or a classification system. Therefore, we recommend that any patient with IBP features who fails to improve after 3 months of an exercise program, for whom you have a high index of suspicion for possible axSpA spectrum disease, receive appropriate ancillary studies and referral for expert consultation.

Exercise and NSAIDs form the basis of treatment

The purpose of treating patients with a suspected axSpA spectrum disorder is to decrease pain and stiffness, improve function and quality of life, and, ideally, halt or slow progression of disease. The only modifiable predictor of progression to axSpA is smoking; as such, encourage tobacco cessation if appropriate.¹⁴

Continue to: Nonpharmacologic treatment...

Nonpharmacologic treatment, such as regular aerobic exercise and strength training, should be prescribed for all patients with axSpA.⁶ Regular exercise is helpful in improving lower back pain, function, and spinal mobility. Combination endurance and strength-training programs are associated with the greatest benefits, and aquatic therapy is better than land-based therapy for pain.¹⁵ That said, recommend land-based exercises over no exercise when pool-based therapy is unavailable.

NSAIDs (eg, ibuprofen 200-800 mg at variable frequency, up to a maximum dose of 2400 mg/d; naproxen 250-500 mg bid) are the core treatment for patients with axSpA, as they improve pain, function, and quality of life.⁶ Both traditional NSAIDs and cyclooxygenase II (COX-II) inhibitors are effective; no differences in efficacy exist between the classes.^6,15,16

Prompt diagnosis of patients with ankylosing spondylitis is important because those diagnosed after significant sacroiliitis is visible are less responsive to treatment.

NSAIDs have been shown to be as safe as placebo for up to 12 weeks of continuous use in patients without gastritis or renal disease.¹⁶ In patients with a gastrointestinal comorbidity, use NSAIDs cautiously.¹⁷

If adequate pain relief is not obtained after 2 to 4 weeks of NSAID use, try a different NSAID prior to escalating treatment.⁶ More research is needed to evaluate the effect of NSAIDs on spinal radiographic progression of disease because of conflicting results of existing studies.¹⁶

Unlike with other rheumatologic disorders, oral glucocorticoids and traditional disease-modifying anti-rheumatic drugs (DMARDs) are not effective in axSpA and should not be prescribed.¹⁸

Continue to: Other agents

Other agents. In patients who continue to have symptoms, or cannot tolerate 12 weeks of NSAIDs, newer biologic DMARDs may be considered. Tumor necrosis factor inhibitors (TNFi) and interleukin-17 inhibitors (IL-17i) have shown the best efficacy.^18,19 In patients with AS, these medications improve pain and function, increase the chance of achieving partial remission of symptoms, and reduce CRP levels and MRI-detectable inflammation of the SI joint and/or spine.^1,19 At this time, these medications are reserved for use in patients with clinical symptoms consistent with, and radiographic evidence of, axSpA, or in patients with nr-axSpA who have elevated CRP levels.¹⁸

For patients diagnosed with axSpA, an elevated CRP, short symptom duration (or young age), and inflammation noted on MRI seem to be the best predictors of a good response to TNFi.²⁰ All patients in whom biologic DMARDS are considered should be referred to a rheumatologist because of cost, potential adverse effects, and stringent indications for use.

Surveil disease progression to prevent complications

We don’t yet know if progression of axSpA is linear or if the process can be slowed or halted with timely treatment. We do know that the natural history of structural progression is low in patients with early nr-axSpA.

Examples of validated online tools that can assist in measuring patient response to treatment and/or progression of disease follow.²¹ They can be used alone or in combination to help monitor treatment and progression of disease.

• The Ankylosing Spondylitis Disease Activity Score (ASDAS) (https://www.asas-group.org/clinical-instruments/asdas-calculator/). This measure of disease activity uses a 5-item patient assessment and CRP level measurement.
• The Bath Ankylosing Spondylitis Functional Index (BASFI) (http://basdai.com/BASFI.php). The BASFI consists of 8 items pertaining to everyday function and 2 items assessing the ability of patients to cope with everyday life.
• The Ankylosing Spondylitis Quality of Life Scale (ASQoL; http://oml.eular.org/sysModules/obxOml/docs/ID_32/ASQoL%20Questionnaire%20English.pdf).The ASQoL is an 18-item questionnaire related to the impact of disease on sleep, mood, motivation, and activities of daily living, among others.

Comorbidities. Patients with axSpA have an increased lifetime risk for cardiovascular disease, osteoporosis, fracture, inflammatory bowel disease, and iritis.⁶ Acute back pain in a patient with axSpA should be evaluated for a fracture and not automatically deemed an axSpA flare.¹³ Obtain a CT scan of the spine for all patients with known spine ankyloses who are suspected of having a fracture (because of the low sensitivity of plain radiography).¹³

Continue to: Prognosis

Prognosis. AS is a progressive long-term medical condition. Patients may experience progressive spinal deformity, hip joint or sacroiliac arthroses, or neurologic compromise after trauma. Reserve surgical referral for patients with spinal deformity that significantly affects quality of life and is severe or progressing despite nonpharmacologic and pharmacologic measures. Refer patients with an unstable spinal fracture for surgical intervention.⁶

Order HLA-B27 and C-reactive protein testing in all patients suspected of having an axial spondyloarthritis spectrum disorder.

Advise patients of available local, national, and international support groups. The National Ankylosis Spondylitis Society (NASS) based in the United Kingdom and the Spondylitis Association of America (SAA) are patient-friendly, nonprofit organizations that provide resources and information to people to help them learn about and cope with their condition.

CASE

You diagnose IBP in this patient and proceed with a work-up. You order x-rays of the back and SI joint, a CRP level, and an HLA-B27 test. X-rays and laboratory studies are negative. The patient is encouraged by your recommendation to start an aerobic and strength training home exercise program. In addition, you prescribe naproxen 500 mg bid and ask the patient to return in 1 month.

On follow-up he states that the naproxen is working well to control his pain. Upon further chart review and questioning, the patient confirms a history of chronic plantar fasciosis and psoriasis that he has controlled with intermittent topical steroids. He denies visual disturbances or gastrointestinal complaints. You refer him to a rheumatologist, where biologic agents are discussed but not prescribed at this time.

CORRESPONDENCE
Carlton J Covey, MD, FAAFP, Nellis Family Medicine Residency Program, 4700 Las Vegas Blvd. North, Nellis AFB, NV 89191; [email protected]

Over the past year through early 2019, the US Preventive Services Task Force made 34 recommendations on 19 different topics. Twenty-six were reaffirmations of recommendations made in previous years (TABLE 1¹); the Task Force attempts to reassess topics every 7 years. Two new topics were addressed with 2 new recommendations, and 6 previous recommendations were revised or reversed (TABLE 2^2-9).

This Practice Alert discusses the new and the changed recommendations. (In 2018, the Practice Alert podcast series covered screening for ovarian cancer [April], prostate cancer [June], and cervical cancer [October], and EKG screening for cardiovascular disease [November].) All current Task Force recommendations are available on the USPSTF Web site.¹

New topics

Perinatal depression prevention

The Task Force recommends that clinicians counsel pregnant women and women in the first year postpartum who are at increased risk for perinatal depression, or refer for such services. The recommendation applies to those who are not diagnosed with depression but are at increased risk.

Perinatal depression can negatively affect both mother and child in several ways and occurs at a rate close to 9% during pregnancy and 37% during the first year postpartum.² The interventions studied by the Task Force included cognitive behavioral therapy and interpersonal therapy; most sessions were initiated in the second trimester of pregnancy and varied in number of sessions and intensity. The Task Force includes the following in the list of risks that should prompt a referral: a history of depression, current depressive symptoms that fall short of that needed for a depression diagnosis, low income, adolescent or single parenthood, recent intimate partner violence, elevated anxiety symptoms, physical or sexual abuse, or a history of significant negative life events. (See “Postpartum anxiety: More common than you think,” in the April issue.)

Atrial fibrillation

The Task Force found insufficient evidence to recommend for or against the use of electrocardiography (EKG) to screen for atrial fibrillation (AF).³ Atrial fibrillation is common, affecting 3% of men and 2% of women between the ages of 65 and 69 years, and it increases in prevalence with age.⁴ It is a major risk factor for stroke, although it is commonly first diagnosed after a stroke. Treatment with anticoagulant therapy reduces the incidence of stroke in patients with symptomatic AF, but this treatment is associated with the risk of major bleeding. The problem in screening for AF with EKG is that it is associated with misdiagnosis, over-treatment, and further testing. The Task Force could not find any direct evidence of the totality of benefits and harms of screening asymptomatic adults with EKG, and it raised the possibility that benefit with less harm might be achieved by screening with pulse palpation and heart auscultation, followed by EKG testing of those with an irregular pulse.

Revisions of previous recommendations

Cervical cancer screening

The Task Force continues to recommend screening for cervical cancer in women 21 to 65 years of age.⁵ The major change in the current recommendation is for women ages 30 to 65 years. For this group, the Task Force now recommends screening every 5 years with high-risk human papillomavirus (hrHPV) testing alone as a possible alternative to screening every 3 years with cytology alone. They also halfheartedly endorse co-testing as an option, even though it may result in more tests and procedures compared with either cytology or hrHPV testing alone, with equal effectiveness. For women ages 21 to 29 years, cervical cytology alone every 3 years is still the only recommended regimen.

Skin cancer prevention

The Task Force made 2 revisions to the 2012 recommendation on preventing skin cancer through behavioral counseling to avoid ultraviolet (UV) radiation.⁶ These recommendations continue to focus on those with fair skin. The first revision: The earliest age at which children (through their guardians) can benefit from counseling on UV avoidance has been lowered from age 10 years to 6 months. The second revision: Some adults older than age 24 can also benefit from such counseling if they have fair skin and other skin cancer risks such as using tanning beds, having a history of sunburns or previous skin cancer, having an increased number of nevi (moles) and atypical nevi, having human immunodeficiency virus (HIV) infection, having received an organ transplant, or having a family history of skin cancer.

Continue to: Those at risk...

Those at risk can reduce their chances of skin cancer by using broad-spectrum sunscreens and sun-protective clothing, and by avoiding sun exposure and indoor tanning beds.

Fall prevention

In a reversal of its 2012 recommendation, the Task Force now recommends against the use of vitamin D supplementation to prevent falls in community-dwelling adults 65 years or older.⁷ In a reanalysis of previous studies on this topic, along with new evidence, the Task Force concluded that vitamin D supplementation offers no benefit for preventing falls in adults who are not vitamin D deficient.

Screening for scoliosis in adolescents

In 2004 the USPSTF recommended against screening for idiopathic scoliosis in children and adolescents 10 to 18 years of age. In its most recent review, the Task Force continued to find no direct evidence of the benefit of screening and inadequate evidence on the long-term benefits of reduction in spinal curvature through exercise, surgery, and bracing. However, following a reanalysis of the potential harms of these treatments and the use of a new analytic framework, the Task Force concluded it is not possible at this time to assess the balance of benefits and harms of screening.⁸

Prostate cancer screening

In its most controversial action, the Task Force reversed its 2012 recommendation against routine prostate-specific antigen–based screening for prostate cancer in men ages 55 to 69 years and now lists this as a “C” recommendation.⁹ The potential benefits of screening include preventing 1.3 deaths from prostate cancer per 1000 men screened over 13 years and approximately 3 cases of metastatic prostate cancer. However, no trials have found a reduction in all-cause mortality from screening. Contrast that with the known harms of screening: 15% false positive results over 10 years; 1% hospitalization rate among those undergoing a prostate biopsy; over-diagnosis and resultant treatment of 20% to 50% of men diagnosed with prostate cancer through screening; and incontinence and erectile dysfunction in 20% and 67%, respectively, of men following prostatectomy.⁹

Evidence is insufficient to recommend for or against the use of electrocardiography in screening for atrial fibrillation.

Based on these outcomes, the Task Force “does not recommend screening for prostate cancer unless men express a preference for screening after being informed of and understanding the benefits and risks.”⁹ The Task Force continues to recommend against screening men ages 70 years and older.

Continue to: The change in this recommendation...

The change in this recommendation and its wording present dilemmas for family physicians: whether to discuss potential screening with all men ages 55 to 69; to selectively discuss it with those at high risk (principally African Americans and those with a strong family history of prostate cancer); or to address the issue only if a patient asks about it. In addition, if a man requests screening, how often should it be performed? Most clinical trials have found equal benefit from testing less frequently than every year, with fewer harms. The Task Force provided little or no guidance on these issues.

Final advice: D recommendations

The Task Force reaffirmed that 7 services have either no benefit or cause more harm than benefit (TABLE 1¹). Family physicians should be familiar with these services, as well as all Task Force D recommendations, and avoid recommending them or providing them. High quality preventive care involves both providing services of proven benefit and avoiding those that do not.

Over the past year through early 2019, the US Preventive Services Task Force made 34 recommendations on 19 different topics. Twenty-six were reaffirmations of recommendations made in previous years (TABLE 1¹); the Task Force attempts to reassess topics every 7 years. Two new topics were addressed with 2 new recommendations, and 6 previous recommendations were revised or reversed (TABLE 2^2-9).

This Practice Alert discusses the new and the changed recommendations. (In 2018, the Practice Alert podcast series covered screening for ovarian cancer [April], prostate cancer [June], and cervical cancer [October], and EKG screening for cardiovascular disease [November].) All current Task Force recommendations are available on the USPSTF Web site.¹

New topics

Perinatal depression prevention

The Task Force recommends that clinicians counsel pregnant women and women in the first year postpartum who are at increased risk for perinatal depression, or refer for such services. The recommendation applies to those who are not diagnosed with depression but are at increased risk.

Perinatal depression can negatively affect both mother and child in several ways and occurs at a rate close to 9% during pregnancy and 37% during the first year postpartum.² The interventions studied by the Task Force included cognitive behavioral therapy and interpersonal therapy; most sessions were initiated in the second trimester of pregnancy and varied in number of sessions and intensity. The Task Force includes the following in the list of risks that should prompt a referral: a history of depression, current depressive symptoms that fall short of that needed for a depression diagnosis, low income, adolescent or single parenthood, recent intimate partner violence, elevated anxiety symptoms, physical or sexual abuse, or a history of significant negative life events. (See “Postpartum anxiety: More common than you think,” in the April issue.)

Atrial fibrillation

The Task Force found insufficient evidence to recommend for or against the use of electrocardiography (EKG) to screen for atrial fibrillation (AF).³ Atrial fibrillation is common, affecting 3% of men and 2% of women between the ages of 65 and 69 years, and it increases in prevalence with age.⁴ It is a major risk factor for stroke, although it is commonly first diagnosed after a stroke. Treatment with anticoagulant therapy reduces the incidence of stroke in patients with symptomatic AF, but this treatment is associated with the risk of major bleeding. The problem in screening for AF with EKG is that it is associated with misdiagnosis, over-treatment, and further testing. The Task Force could not find any direct evidence of the totality of benefits and harms of screening asymptomatic adults with EKG, and it raised the possibility that benefit with less harm might be achieved by screening with pulse palpation and heart auscultation, followed by EKG testing of those with an irregular pulse.

Revisions of previous recommendations

Cervical cancer screening

The Task Force continues to recommend screening for cervical cancer in women 21 to 65 years of age.⁵ The major change in the current recommendation is for women ages 30 to 65 years. For this group, the Task Force now recommends screening every 5 years with high-risk human papillomavirus (hrHPV) testing alone as a possible alternative to screening every 3 years with cytology alone. They also halfheartedly endorse co-testing as an option, even though it may result in more tests and procedures compared with either cytology or hrHPV testing alone, with equal effectiveness. For women ages 21 to 29 years, cervical cytology alone every 3 years is still the only recommended regimen.

Skin cancer prevention

The Task Force made 2 revisions to the 2012 recommendation on preventing skin cancer through behavioral counseling to avoid ultraviolet (UV) radiation.⁶ These recommendations continue to focus on those with fair skin. The first revision: The earliest age at which children (through their guardians) can benefit from counseling on UV avoidance has been lowered from age 10 years to 6 months. The second revision: Some adults older than age 24 can also benefit from such counseling if they have fair skin and other skin cancer risks such as using tanning beds, having a history of sunburns or previous skin cancer, having an increased number of nevi (moles) and atypical nevi, having human immunodeficiency virus (HIV) infection, having received an organ transplant, or having a family history of skin cancer.

Continue to: Those at risk...

Those at risk can reduce their chances of skin cancer by using broad-spectrum sunscreens and sun-protective clothing, and by avoiding sun exposure and indoor tanning beds.

Fall prevention

In a reversal of its 2012 recommendation, the Task Force now recommends against the use of vitamin D supplementation to prevent falls in community-dwelling adults 65 years or older.⁷ In a reanalysis of previous studies on this topic, along with new evidence, the Task Force concluded that vitamin D supplementation offers no benefit for preventing falls in adults who are not vitamin D deficient.

Screening for scoliosis in adolescents

In 2004 the USPSTF recommended against screening for idiopathic scoliosis in children and adolescents 10 to 18 years of age. In its most recent review, the Task Force continued to find no direct evidence of the benefit of screening and inadequate evidence on the long-term benefits of reduction in spinal curvature through exercise, surgery, and bracing. However, following a reanalysis of the potential harms of these treatments and the use of a new analytic framework, the Task Force concluded it is not possible at this time to assess the balance of benefits and harms of screening.⁸

Prostate cancer screening

In its most controversial action, the Task Force reversed its 2012 recommendation against routine prostate-specific antigen–based screening for prostate cancer in men ages 55 to 69 years and now lists this as a “C” recommendation.⁹ The potential benefits of screening include preventing 1.3 deaths from prostate cancer per 1000 men screened over 13 years and approximately 3 cases of metastatic prostate cancer. However, no trials have found a reduction in all-cause mortality from screening. Contrast that with the known harms of screening: 15% false positive results over 10 years; 1% hospitalization rate among those undergoing a prostate biopsy; over-diagnosis and resultant treatment of 20% to 50% of men diagnosed with prostate cancer through screening; and incontinence and erectile dysfunction in 20% and 67%, respectively, of men following prostatectomy.⁹

Evidence is insufficient to recommend for or against the use of electrocardiography in screening for atrial fibrillation.

Based on these outcomes, the Task Force “does not recommend screening for prostate cancer unless men express a preference for screening after being informed of and understanding the benefits and risks.”⁹ The Task Force continues to recommend against screening men ages 70 years and older.

Continue to: The change in this recommendation...

The change in this recommendation and its wording present dilemmas for family physicians: whether to discuss potential screening with all men ages 55 to 69; to selectively discuss it with those at high risk (principally African Americans and those with a strong family history of prostate cancer); or to address the issue only if a patient asks about it. In addition, if a man requests screening, how often should it be performed? Most clinical trials have found equal benefit from testing less frequently than every year, with fewer harms. The Task Force provided little or no guidance on these issues.

Final advice: D recommendations

The Task Force reaffirmed that 7 services have either no benefit or cause more harm than benefit (TABLE 1¹). Family physicians should be familiar with these services, as well as all Task Force D recommendations, and avoid recommending them or providing them. High quality preventive care involves both providing services of proven benefit and avoiding those that do not.

Over the past year through early 2019, the US Preventive Services Task Force made 34 recommendations on 19 different topics. Twenty-six were reaffirmations of recommendations made in previous years (TABLE 1¹); the Task Force attempts to reassess topics every 7 years. Two new topics were addressed with 2 new recommendations, and 6 previous recommendations were revised or reversed (TABLE 2^2-9).

This Practice Alert discusses the new and the changed recommendations. (In 2018, the Practice Alert podcast series covered screening for ovarian cancer [April], prostate cancer [June], and cervical cancer [October], and EKG screening for cardiovascular disease [November].) All current Task Force recommendations are available on the USPSTF Web site.¹

New topics

Perinatal depression prevention

The Task Force recommends that clinicians counsel pregnant women and women in the first year postpartum who are at increased risk for perinatal depression, or refer for such services. The recommendation applies to those who are not diagnosed with depression but are at increased risk.

Perinatal depression can negatively affect both mother and child in several ways and occurs at a rate close to 9% during pregnancy and 37% during the first year postpartum.² The interventions studied by the Task Force included cognitive behavioral therapy and interpersonal therapy; most sessions were initiated in the second trimester of pregnancy and varied in number of sessions and intensity. The Task Force includes the following in the list of risks that should prompt a referral: a history of depression, current depressive symptoms that fall short of that needed for a depression diagnosis, low income, adolescent or single parenthood, recent intimate partner violence, elevated anxiety symptoms, physical or sexual abuse, or a history of significant negative life events. (See “Postpartum anxiety: More common than you think,” in the April issue.)

Atrial fibrillation

The Task Force found insufficient evidence to recommend for or against the use of electrocardiography (EKG) to screen for atrial fibrillation (AF).³ Atrial fibrillation is common, affecting 3% of men and 2% of women between the ages of 65 and 69 years, and it increases in prevalence with age.⁴ It is a major risk factor for stroke, although it is commonly first diagnosed after a stroke. Treatment with anticoagulant therapy reduces the incidence of stroke in patients with symptomatic AF, but this treatment is associated with the risk of major bleeding. The problem in screening for AF with EKG is that it is associated with misdiagnosis, over-treatment, and further testing. The Task Force could not find any direct evidence of the totality of benefits and harms of screening asymptomatic adults with EKG, and it raised the possibility that benefit with less harm might be achieved by screening with pulse palpation and heart auscultation, followed by EKG testing of those with an irregular pulse.

Revisions of previous recommendations

Cervical cancer screening

The Task Force continues to recommend screening for cervical cancer in women 21 to 65 years of age.⁵ The major change in the current recommendation is for women ages 30 to 65 years. For this group, the Task Force now recommends screening every 5 years with high-risk human papillomavirus (hrHPV) testing alone as a possible alternative to screening every 3 years with cytology alone. They also halfheartedly endorse co-testing as an option, even though it may result in more tests and procedures compared with either cytology or hrHPV testing alone, with equal effectiveness. For women ages 21 to 29 years, cervical cytology alone every 3 years is still the only recommended regimen.

Skin cancer prevention

The Task Force made 2 revisions to the 2012 recommendation on preventing skin cancer through behavioral counseling to avoid ultraviolet (UV) radiation.⁶ These recommendations continue to focus on those with fair skin. The first revision: The earliest age at which children (through their guardians) can benefit from counseling on UV avoidance has been lowered from age 10 years to 6 months. The second revision: Some adults older than age 24 can also benefit from such counseling if they have fair skin and other skin cancer risks such as using tanning beds, having a history of sunburns or previous skin cancer, having an increased number of nevi (moles) and atypical nevi, having human immunodeficiency virus (HIV) infection, having received an organ transplant, or having a family history of skin cancer.

Continue to: Those at risk...

Those at risk can reduce their chances of skin cancer by using broad-spectrum sunscreens and sun-protective clothing, and by avoiding sun exposure and indoor tanning beds.

Fall prevention

In a reversal of its 2012 recommendation, the Task Force now recommends against the use of vitamin D supplementation to prevent falls in community-dwelling adults 65 years or older.⁷ In a reanalysis of previous studies on this topic, along with new evidence, the Task Force concluded that vitamin D supplementation offers no benefit for preventing falls in adults who are not vitamin D deficient.

Screening for scoliosis in adolescents

In 2004 the USPSTF recommended against screening for idiopathic scoliosis in children and adolescents 10 to 18 years of age. In its most recent review, the Task Force continued to find no direct evidence of the benefit of screening and inadequate evidence on the long-term benefits of reduction in spinal curvature through exercise, surgery, and bracing. However, following a reanalysis of the potential harms of these treatments and the use of a new analytic framework, the Task Force concluded it is not possible at this time to assess the balance of benefits and harms of screening.⁸

Prostate cancer screening

In its most controversial action, the Task Force reversed its 2012 recommendation against routine prostate-specific antigen–based screening for prostate cancer in men ages 55 to 69 years and now lists this as a “C” recommendation.⁹ The potential benefits of screening include preventing 1.3 deaths from prostate cancer per 1000 men screened over 13 years and approximately 3 cases of metastatic prostate cancer. However, no trials have found a reduction in all-cause mortality from screening. Contrast that with the known harms of screening: 15% false positive results over 10 years; 1% hospitalization rate among those undergoing a prostate biopsy; over-diagnosis and resultant treatment of 20% to 50% of men diagnosed with prostate cancer through screening; and incontinence and erectile dysfunction in 20% and 67%, respectively, of men following prostatectomy.⁹

Evidence is insufficient to recommend for or against the use of electrocardiography in screening for atrial fibrillation.

Based on these outcomes, the Task Force “does not recommend screening for prostate cancer unless men express a preference for screening after being informed of and understanding the benefits and risks.”⁹ The Task Force continues to recommend against screening men ages 70 years and older.

Continue to: The change in this recommendation...

The change in this recommendation and its wording present dilemmas for family physicians: whether to discuss potential screening with all men ages 55 to 69; to selectively discuss it with those at high risk (principally African Americans and those with a strong family history of prostate cancer); or to address the issue only if a patient asks about it. In addition, if a man requests screening, how often should it be performed? Most clinical trials have found equal benefit from testing less frequently than every year, with fewer harms. The Task Force provided little or no guidance on these issues.

Final advice: D recommendations

The Task Force reaffirmed that 7 services have either no benefit or cause more harm than benefit (TABLE 1¹). Family physicians should be familiar with these services, as well as all Task Force D recommendations, and avoid recommending them or providing them. High quality preventive care involves both providing services of proven benefit and avoiding those that do not.

CASE

A 22-year-old active-duty man presented with left hallux pain, which he had experienced for several years due to an “ingrown toenail.” During the 3 to 4 months prior to presentation, his pain had progressed to the point that he had difficulty with weight-bearing activities. Several weeks prior to evaluation, he tried removing a portion of the nail himself with nail clippers and a pocket knife, but the symptoms persisted.

A skin exam revealed inflamed hypertrophic skin on the medial and lateral border of the toenail without exudate (FIGURE 1A). The patient was given a diagnosis of recurrent onychocryptosis without paronychia. He reported having a similar occurrence 1 to 2 years earlier, which had been treated by his primary care physician via total nail avulsion.

How would you proceed with his care?

Onychocryptosis, also known as an ingrown toenail, is a relatively common condition that can be treated with several nonsurgical and surgical approaches. It occurs when the nail plate punctures the periungual skin, usually on the hallux. Onychocryptosis may be caused by close-trimmed nails with a free edge that are allowed to enter the lateral nail fold. This results in a cascade of inflammatory and infectious processes and may result in paronychia. The inflamed toe skin will often grow over the lateral nail, which further exacerbates the condition. Mild to moderate lesions have limited pain, redness, and swelling with little or no discharge. Moderate to severe lesions have significant pain, redness, swelling, discharge, and/or persistent symptoms despite appropriate conservative therapies.

The condition may manifest at any age, although it is more common in adolescents and young adults. Onychocryptosis is slightly more common in males.¹ It may present as a chief complaint, although many cases will likely be discovered incidentally on a skin exam. Although there is no firm evidence of causative factors, possible risk factors include tight-fitting shoes, repetitive activities/sports, poor foot hygiene, hyperhidrosis, genetic predisposition, obesity, and lower-extremity edema.² Patients often exacerbate the problem with home treatments designed to trim the nail as short as possible. Comparison of symptomatic vs control patients has failed to demonstrate any systematic difference between the nails themselves. This suggests that treatment may not be effective if it is simply directed at controlling nail abnormalities.^3,4

Conservative therapy

Conservative therapy should be considered first-line treatment for mild to moderate cases of onychocryptosis. The following are conservative therapy options.⁵

Proper nail trimming. Advise the patient to allow the nail to grow past the lateral nail fold and to keep it trimmed long so that the overgrowing toe skin cannot encroach on the free edge of the nail. The growth rate of the toenail is approximately 1.62 mm/month—something you may want to mention to the patient so that he or she will have a sense of the estimated duration of therapy.⁶ Also, the patient may need to implement the following other measures, while the nail is allowed to grow.

Continue to: Skin-softening techniques

Skin-softening techniques. Encourage the patient to apply warm compresses or to soak the toe in warm water for 10 to 20 minutes a day.

Barriers may be inserted between the nail and the periungual skin. Daily intermittent barriers may be used to lift the nail away from the lateral nail fold during regular hygiene activities. Tell the patient that a continuous barrier may be created using gauze or any variety of dental floss placed between the nail and the lateral nail fold, then secured in place with tape and changed daily.

Gutter splint. The gutter splint consists of a plastic tube that has been slit longitudinally from bottom to top with iris scissors or a scalpel. One end is then cut diagonally for smooth insertion between the nail edge and the periungual skin. When placed, the gutter splint lies longitudinally along the edge of the nail, providing a barrier to protect the toe during nail growth. The tube may be obtained by trimming a sterilized vinyl intravenous drip infusion, the catheter from an 18-gauge or larger needle (with the needle removed), or a filter straw. This tube can be affixed with adhesive tape, sutures, or cyanoacrylate.⁷

Patient-controlled taping. An adhesive tape such as 1-inch silk tape is placed on the symptomatic edge of the lateral nail fold and traction is applied. The tape is then wrapped around the toe and affixed such that the lateral nail fold is pulled away from the nail.⁸

Medications. Many practitioners use high-potency topical steroids, although evidence for their effectiveness is lacking. Oral antibiotics are unnecessary.

Continue to: One disadvantage of conservative therapy is...

Conservative therapies focus on allowing the nail to grow past the lateral nail fold and keeping it trimmed long so that the overgrowing toe skin can’t encroach on the free edge of the nail.

One disadvantage of conservative therapy is that the patient must wait for nail growth before symptom resolution is achieved. In cases where the patient requires immediate symptom resolution, surgical therapies can be used (such as nail edge excision).

Surgical therapy

Surgery is more effective than nonsurgical therapies in preventing recurrence^2,9 and is indicated for severe cases of onychocryptosis or for patients who do not respond to a trial of at least 3 months of conservative care.

While there are no universally accepted contraindications to surgical toenail procedures, caution should be taken with patients who have poor healing potential of the feet (eg, chronic vasculopathy or neuropathy). That said, when patients with diabetes have undergone surgical toenail procedures, the research indicates that they have not had worse outcomes.^10,11

Approximately 6 weeks after the Vandenbos procedure, the wound should be healed completely with the nail remaining above the skin.

The following options for surgical therapy of onychocryptosis are considered safe; however, each has variable effectiveness. Each procedure should be performed under local anesthesia, typically as a digital nerve block. The toe should be cleansed prior to any surgical intervention, and clean procedure precautions should be employed. Of the procedures listed here, only phenolization and the Vandenbos procedure are considered definitive treatments for onychocryptosis.⁵

Total nail removal without matricectomy. In this procedure, the nail is removed entirely, but the nail matrix is not destroyed. The nail regrows in the same dimensions as it had previously, but during the time it is absent the nail bed tends to contract longitudinally and transversely, increasing the likelihood that new nail growth will cause recurrence of symptoms.⁵ Due to a recurrence rate of > 70%, total nail removal without matricectomy is not recommended as monotherapy for ingrown toenails.⁹

Continue to: Nail edge excision without mactricectomy

Nail edge excision without matricectomy. This procedure involves removing one-quarter to one-third of the nail from the symptomatic edge. This procedure takes little time and is easy to perform. Recurrence rates are > 70% for the same reasons as outlined above.⁹ (Often during preparation for this procedure, a loose shard of nail is observed puncturing the periungual skin. Removal of this single aberrant portion of nail is frequently curative in and of itself.) Patients typically report rapid relief of symptoms, so this procedure may be favored when patients do not have the time or desire to attempt more definitive therapy. However, patients should be advised of the high recurrence rate.

Nail excision with matricectomy using phenol (ie, phenolization). In this procedure, the nail is avulsed, and the matrix is destroyed with phenol (80%-88%).^9,12 Typically, this is performed only on the symptomatic edge of the nail. The phenol should be applied for 1 to 3 minutes using a cotton-tipped applicator saturated in the solution. Recurrence rates are as low as 2% when the phenol is applied for 3 minutes, although the risk for symptomatic drainage of the wound after 2 weeks is > 50%. When applied for only 1 minute, the recurrence rate is approximately 12% but the risk for drainage at 2 weeks is also 12%.¹² (Other studies have reported recurrence rates up to 50%.¹³)

Surgical therapies are indicated for severe cases of onychocryptosis or for those who do not respond to a 3-month trial of conservative care.

While phenolization is relatively quick and simple—and is associated with good cure rates—it causes pain and disability during the healing process and takes several weeks to heal. Phenolization also has a slightly increased risk for infection when compared to nail excision without matricectomy. Giving antibiotics before or following the procedure does not appear to reduce this risk.⁷ If the matrix is incompletely destroyed, a new nail spicule may grow along the lateral nail edge and a repeat procedure may be required.⁷ When properly performed, the nail will be narrower but should otherwise maintain a more-or-less normal appearance. The use of phenolization for the treatment of onychocryptosis in the pediatric population has been found to be successful, as well.¹⁴

The Vandenbos procedure. This procedure involves removing a large amount of skin from the lateral nail fold and allowing it to heal secondarily. When performed correctly, this procedure has a very low recurrence rate, with no cases of recurrence in nearly 1200 patients reported in the literature.¹⁵ The cosmetic results are generally superior to the other surgical methods described here⁵ and patient satisfaction is high.¹⁵ It has been used with similar effectiveness in children.¹⁶

The Vandenbos procedure can definitively treat onychocryptosis with a good cosmetic outcome.

Full recovery takes about 6 weeks. Overall, the Vandenbos procedure can definitively treat the condition with a good cosmetic outcome. (See “How to perform the Vandenbos procedure.”)

Continue to: SIDEBAR

CORRESPONDENCE
Stephen K. Stacey, DO, Chief Resident, Peak Vista Family Medicine Residency Program, 340 Printers Parkway, Colorado Springs, CO 80910; [email protected].

CASE

A 22-year-old active-duty man presented with left hallux pain, which he had experienced for several years due to an “ingrown toenail.” During the 3 to 4 months prior to presentation, his pain had progressed to the point that he had difficulty with weight-bearing activities. Several weeks prior to evaluation, he tried removing a portion of the nail himself with nail clippers and a pocket knife, but the symptoms persisted.

A skin exam revealed inflamed hypertrophic skin on the medial and lateral border of the toenail without exudate (FIGURE 1A). The patient was given a diagnosis of recurrent onychocryptosis without paronychia. He reported having a similar occurrence 1 to 2 years earlier, which had been treated by his primary care physician via total nail avulsion.

How would you proceed with his care?

Onychocryptosis, also known as an ingrown toenail, is a relatively common condition that can be treated with several nonsurgical and surgical approaches. It occurs when the nail plate punctures the periungual skin, usually on the hallux. Onychocryptosis may be caused by close-trimmed nails with a free edge that are allowed to enter the lateral nail fold. This results in a cascade of inflammatory and infectious processes and may result in paronychia. The inflamed toe skin will often grow over the lateral nail, which further exacerbates the condition. Mild to moderate lesions have limited pain, redness, and swelling with little or no discharge. Moderate to severe lesions have significant pain, redness, swelling, discharge, and/or persistent symptoms despite appropriate conservative therapies.

The condition may manifest at any age, although it is more common in adolescents and young adults. Onychocryptosis is slightly more common in males.¹ It may present as a chief complaint, although many cases will likely be discovered incidentally on a skin exam. Although there is no firm evidence of causative factors, possible risk factors include tight-fitting shoes, repetitive activities/sports, poor foot hygiene, hyperhidrosis, genetic predisposition, obesity, and lower-extremity edema.² Patients often exacerbate the problem with home treatments designed to trim the nail as short as possible. Comparison of symptomatic vs control patients has failed to demonstrate any systematic difference between the nails themselves. This suggests that treatment may not be effective if it is simply directed at controlling nail abnormalities.^3,4

Conservative therapy

Conservative therapy should be considered first-line treatment for mild to moderate cases of onychocryptosis. The following are conservative therapy options.⁵

Proper nail trimming. Advise the patient to allow the nail to grow past the lateral nail fold and to keep it trimmed long so that the overgrowing toe skin cannot encroach on the free edge of the nail. The growth rate of the toenail is approximately 1.62 mm/month—something you may want to mention to the patient so that he or she will have a sense of the estimated duration of therapy.⁶ Also, the patient may need to implement the following other measures, while the nail is allowed to grow.

Continue to: Skin-softening techniques

Skin-softening techniques. Encourage the patient to apply warm compresses or to soak the toe in warm water for 10 to 20 minutes a day.

Barriers may be inserted between the nail and the periungual skin. Daily intermittent barriers may be used to lift the nail away from the lateral nail fold during regular hygiene activities. Tell the patient that a continuous barrier may be created using gauze or any variety of dental floss placed between the nail and the lateral nail fold, then secured in place with tape and changed daily.

Gutter splint. The gutter splint consists of a plastic tube that has been slit longitudinally from bottom to top with iris scissors or a scalpel. One end is then cut diagonally for smooth insertion between the nail edge and the periungual skin. When placed, the gutter splint lies longitudinally along the edge of the nail, providing a barrier to protect the toe during nail growth. The tube may be obtained by trimming a sterilized vinyl intravenous drip infusion, the catheter from an 18-gauge or larger needle (with the needle removed), or a filter straw. This tube can be affixed with adhesive tape, sutures, or cyanoacrylate.⁷

Patient-controlled taping. An adhesive tape such as 1-inch silk tape is placed on the symptomatic edge of the lateral nail fold and traction is applied. The tape is then wrapped around the toe and affixed such that the lateral nail fold is pulled away from the nail.⁸

Medications. Many practitioners use high-potency topical steroids, although evidence for their effectiveness is lacking. Oral antibiotics are unnecessary.

Continue to: One disadvantage of conservative therapy is...

Conservative therapies focus on allowing the nail to grow past the lateral nail fold and keeping it trimmed long so that the overgrowing toe skin can’t encroach on the free edge of the nail.

One disadvantage of conservative therapy is that the patient must wait for nail growth before symptom resolution is achieved. In cases where the patient requires immediate symptom resolution, surgical therapies can be used (such as nail edge excision).

Surgical therapy

Surgery is more effective than nonsurgical therapies in preventing recurrence^2,9 and is indicated for severe cases of onychocryptosis or for patients who do not respond to a trial of at least 3 months of conservative care.

While there are no universally accepted contraindications to surgical toenail procedures, caution should be taken with patients who have poor healing potential of the feet (eg, chronic vasculopathy or neuropathy). That said, when patients with diabetes have undergone surgical toenail procedures, the research indicates that they have not had worse outcomes.^10,11

Approximately 6 weeks after the Vandenbos procedure, the wound should be healed completely with the nail remaining above the skin.

The following options for surgical therapy of onychocryptosis are considered safe; however, each has variable effectiveness. Each procedure should be performed under local anesthesia, typically as a digital nerve block. The toe should be cleansed prior to any surgical intervention, and clean procedure precautions should be employed. Of the procedures listed here, only phenolization and the Vandenbos procedure are considered definitive treatments for onychocryptosis.⁵

Total nail removal without matricectomy. In this procedure, the nail is removed entirely, but the nail matrix is not destroyed. The nail regrows in the same dimensions as it had previously, but during the time it is absent the nail bed tends to contract longitudinally and transversely, increasing the likelihood that new nail growth will cause recurrence of symptoms.⁵ Due to a recurrence rate of > 70%, total nail removal without matricectomy is not recommended as monotherapy for ingrown toenails.⁹

Continue to: Nail edge excision without mactricectomy

Nail edge excision without matricectomy. This procedure involves removing one-quarter to one-third of the nail from the symptomatic edge. This procedure takes little time and is easy to perform. Recurrence rates are > 70% for the same reasons as outlined above.⁹ (Often during preparation for this procedure, a loose shard of nail is observed puncturing the periungual skin. Removal of this single aberrant portion of nail is frequently curative in and of itself.) Patients typically report rapid relief of symptoms, so this procedure may be favored when patients do not have the time or desire to attempt more definitive therapy. However, patients should be advised of the high recurrence rate.

Nail excision with matricectomy using phenol (ie, phenolization). In this procedure, the nail is avulsed, and the matrix is destroyed with phenol (80%-88%).^9,12 Typically, this is performed only on the symptomatic edge of the nail. The phenol should be applied for 1 to 3 minutes using a cotton-tipped applicator saturated in the solution. Recurrence rates are as low as 2% when the phenol is applied for 3 minutes, although the risk for symptomatic drainage of the wound after 2 weeks is > 50%. When applied for only 1 minute, the recurrence rate is approximately 12% but the risk for drainage at 2 weeks is also 12%.¹² (Other studies have reported recurrence rates up to 50%.¹³)

Surgical therapies are indicated for severe cases of onychocryptosis or for those who do not respond to a 3-month trial of conservative care.

While phenolization is relatively quick and simple—and is associated with good cure rates—it causes pain and disability during the healing process and takes several weeks to heal. Phenolization also has a slightly increased risk for infection when compared to nail excision without matricectomy. Giving antibiotics before or following the procedure does not appear to reduce this risk.⁷ If the matrix is incompletely destroyed, a new nail spicule may grow along the lateral nail edge and a repeat procedure may be required.⁷ When properly performed, the nail will be narrower but should otherwise maintain a more-or-less normal appearance. The use of phenolization for the treatment of onychocryptosis in the pediatric population has been found to be successful, as well.¹⁴

The Vandenbos procedure. This procedure involves removing a large amount of skin from the lateral nail fold and allowing it to heal secondarily. When performed correctly, this procedure has a very low recurrence rate, with no cases of recurrence in nearly 1200 patients reported in the literature.¹⁵ The cosmetic results are generally superior to the other surgical methods described here⁵ and patient satisfaction is high.¹⁵ It has been used with similar effectiveness in children.¹⁶

The Vandenbos procedure can definitively treat onychocryptosis with a good cosmetic outcome.

Full recovery takes about 6 weeks. Overall, the Vandenbos procedure can definitively treat the condition with a good cosmetic outcome. (See “How to perform the Vandenbos procedure.”)

Continue to: SIDEBAR

CORRESPONDENCE
Stephen K. Stacey, DO, Chief Resident, Peak Vista Family Medicine Residency Program, 340 Printers Parkway, Colorado Springs, CO 80910; [email protected].

CASE

A 22-year-old active-duty man presented with left hallux pain, which he had experienced for several years due to an “ingrown toenail.” During the 3 to 4 months prior to presentation, his pain had progressed to the point that he had difficulty with weight-bearing activities. Several weeks prior to evaluation, he tried removing a portion of the nail himself with nail clippers and a pocket knife, but the symptoms persisted.

A skin exam revealed inflamed hypertrophic skin on the medial and lateral border of the toenail without exudate (FIGURE 1A). The patient was given a diagnosis of recurrent onychocryptosis without paronychia. He reported having a similar occurrence 1 to 2 years earlier, which had been treated by his primary care physician via total nail avulsion.

How would you proceed with his care?

Onychocryptosis, also known as an ingrown toenail, is a relatively common condition that can be treated with several nonsurgical and surgical approaches. It occurs when the nail plate punctures the periungual skin, usually on the hallux. Onychocryptosis may be caused by close-trimmed nails with a free edge that are allowed to enter the lateral nail fold. This results in a cascade of inflammatory and infectious processes and may result in paronychia. The inflamed toe skin will often grow over the lateral nail, which further exacerbates the condition. Mild to moderate lesions have limited pain, redness, and swelling with little or no discharge. Moderate to severe lesions have significant pain, redness, swelling, discharge, and/or persistent symptoms despite appropriate conservative therapies.

The condition may manifest at any age, although it is more common in adolescents and young adults. Onychocryptosis is slightly more common in males.¹ It may present as a chief complaint, although many cases will likely be discovered incidentally on a skin exam. Although there is no firm evidence of causative factors, possible risk factors include tight-fitting shoes, repetitive activities/sports, poor foot hygiene, hyperhidrosis, genetic predisposition, obesity, and lower-extremity edema.² Patients often exacerbate the problem with home treatments designed to trim the nail as short as possible. Comparison of symptomatic vs control patients has failed to demonstrate any systematic difference between the nails themselves. This suggests that treatment may not be effective if it is simply directed at controlling nail abnormalities.^3,4

Conservative therapy

Conservative therapy should be considered first-line treatment for mild to moderate cases of onychocryptosis. The following are conservative therapy options.⁵

Proper nail trimming. Advise the patient to allow the nail to grow past the lateral nail fold and to keep it trimmed long so that the overgrowing toe skin cannot encroach on the free edge of the nail. The growth rate of the toenail is approximately 1.62 mm/month—something you may want to mention to the patient so that he or she will have a sense of the estimated duration of therapy.⁶ Also, the patient may need to implement the following other measures, while the nail is allowed to grow.

Continue to: Skin-softening techniques

Skin-softening techniques. Encourage the patient to apply warm compresses or to soak the toe in warm water for 10 to 20 minutes a day.

Barriers may be inserted between the nail and the periungual skin. Daily intermittent barriers may be used to lift the nail away from the lateral nail fold during regular hygiene activities. Tell the patient that a continuous barrier may be created using gauze or any variety of dental floss placed between the nail and the lateral nail fold, then secured in place with tape and changed daily.

Gutter splint. The gutter splint consists of a plastic tube that has been slit longitudinally from bottom to top with iris scissors or a scalpel. One end is then cut diagonally for smooth insertion between the nail edge and the periungual skin. When placed, the gutter splint lies longitudinally along the edge of the nail, providing a barrier to protect the toe during nail growth. The tube may be obtained by trimming a sterilized vinyl intravenous drip infusion, the catheter from an 18-gauge or larger needle (with the needle removed), or a filter straw. This tube can be affixed with adhesive tape, sutures, or cyanoacrylate.⁷

Patient-controlled taping. An adhesive tape such as 1-inch silk tape is placed on the symptomatic edge of the lateral nail fold and traction is applied. The tape is then wrapped around the toe and affixed such that the lateral nail fold is pulled away from the nail.⁸

Medications. Many practitioners use high-potency topical steroids, although evidence for their effectiveness is lacking. Oral antibiotics are unnecessary.

Continue to: One disadvantage of conservative therapy is...

Conservative therapies focus on allowing the nail to grow past the lateral nail fold and keeping it trimmed long so that the overgrowing toe skin can’t encroach on the free edge of the nail.

One disadvantage of conservative therapy is that the patient must wait for nail growth before symptom resolution is achieved. In cases where the patient requires immediate symptom resolution, surgical therapies can be used (such as nail edge excision).

Surgical therapy

Surgery is more effective than nonsurgical therapies in preventing recurrence^2,9 and is indicated for severe cases of onychocryptosis or for patients who do not respond to a trial of at least 3 months of conservative care.

While there are no universally accepted contraindications to surgical toenail procedures, caution should be taken with patients who have poor healing potential of the feet (eg, chronic vasculopathy or neuropathy). That said, when patients with diabetes have undergone surgical toenail procedures, the research indicates that they have not had worse outcomes.^10,11

Approximately 6 weeks after the Vandenbos procedure, the wound should be healed completely with the nail remaining above the skin.

The following options for surgical therapy of onychocryptosis are considered safe; however, each has variable effectiveness. Each procedure should be performed under local anesthesia, typically as a digital nerve block. The toe should be cleansed prior to any surgical intervention, and clean procedure precautions should be employed. Of the procedures listed here, only phenolization and the Vandenbos procedure are considered definitive treatments for onychocryptosis.⁵

Total nail removal without matricectomy. In this procedure, the nail is removed entirely, but the nail matrix is not destroyed. The nail regrows in the same dimensions as it had previously, but during the time it is absent the nail bed tends to contract longitudinally and transversely, increasing the likelihood that new nail growth will cause recurrence of symptoms.⁵ Due to a recurrence rate of > 70%, total nail removal without matricectomy is not recommended as monotherapy for ingrown toenails.⁹

Continue to: Nail edge excision without mactricectomy

Nail edge excision without matricectomy. This procedure involves removing one-quarter to one-third of the nail from the symptomatic edge. This procedure takes little time and is easy to perform. Recurrence rates are > 70% for the same reasons as outlined above.⁹ (Often during preparation for this procedure, a loose shard of nail is observed puncturing the periungual skin. Removal of this single aberrant portion of nail is frequently curative in and of itself.) Patients typically report rapid relief of symptoms, so this procedure may be favored when patients do not have the time or desire to attempt more definitive therapy. However, patients should be advised of the high recurrence rate.

Nail excision with matricectomy using phenol (ie, phenolization). In this procedure, the nail is avulsed, and the matrix is destroyed with phenol (80%-88%).^9,12 Typically, this is performed only on the symptomatic edge of the nail. The phenol should be applied for 1 to 3 minutes using a cotton-tipped applicator saturated in the solution. Recurrence rates are as low as 2% when the phenol is applied for 3 minutes, although the risk for symptomatic drainage of the wound after 2 weeks is > 50%. When applied for only 1 minute, the recurrence rate is approximately 12% but the risk for drainage at 2 weeks is also 12%.¹² (Other studies have reported recurrence rates up to 50%.¹³)

Surgical therapies are indicated for severe cases of onychocryptosis or for those who do not respond to a 3-month trial of conservative care.

While phenolization is relatively quick and simple—and is associated with good cure rates—it causes pain and disability during the healing process and takes several weeks to heal. Phenolization also has a slightly increased risk for infection when compared to nail excision without matricectomy. Giving antibiotics before or following the procedure does not appear to reduce this risk.⁷ If the matrix is incompletely destroyed, a new nail spicule may grow along the lateral nail edge and a repeat procedure may be required.⁷ When properly performed, the nail will be narrower but should otherwise maintain a more-or-less normal appearance. The use of phenolization for the treatment of onychocryptosis in the pediatric population has been found to be successful, as well.¹⁴

The Vandenbos procedure. This procedure involves removing a large amount of skin from the lateral nail fold and allowing it to heal secondarily. When performed correctly, this procedure has a very low recurrence rate, with no cases of recurrence in nearly 1200 patients reported in the literature.¹⁵ The cosmetic results are generally superior to the other surgical methods described here⁵ and patient satisfaction is high.¹⁵ It has been used with similar effectiveness in children.¹⁶

The Vandenbos procedure can definitively treat onychocryptosis with a good cosmetic outcome.

Full recovery takes about 6 weeks. Overall, the Vandenbos procedure can definitively treat the condition with a good cosmetic outcome. (See “How to perform the Vandenbos procedure.”)

Continue to: SIDEBAR

CORRESPONDENCE
Stephen K. Stacey, DO, Chief Resident, Peak Vista Family Medicine Residency Program, 340 Printers Parkway, Colorado Springs, CO 80910; [email protected].

A new cholesterol guideline¹ builds on the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol guidelines,² which were a major paradigm shift in the evaluation and management of blood cholesterol levels and risk for atherosclerotic cardiovascular disease (ASCVD). The work was presented (and simultaneously published) on November 10, 2018, at the annual AHA Scientific Sessions in Chicago. Full text,¹ an executive summary,³ and accompanying systematic review of evidence⁴ are available online.

The 2018 AHA/ACC cholesterol guideline represents a step forward in ASCVD prevention—especially in primary prevention, where it provides guidance for risk refinement and personalization. In this article, we mine the details of what has changed and what is new in this guideline so that you can prepare to adopt the recommendations in your practice.

IMAGE: © JOE GORMAN

2013 and 2018 guidelines: Similarities, differences

As in earlier iterations, the 2018 guideline emphasizes healthy lifestyle across the life-course as the basis of ASCVD prevention—as elaborated in the 2013 AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk.⁵ In contrast to the 2013 guidelines,² the 2018 guideline is more comprehensive and more personalized, focusing on risk assessment for individual patients, rather than simply providing population-based approaches. Moreover, the guideline isn’t limited to adults: It makes recommendations pertaining to children and adolescents.¹

TABLE 1^1,2 compares the most important differences between the 2013 and 2018 guidelines.

In contrast to the 2013 guidelines, the 2018 guideline is more comprehensive and more personalized, focusing on risk assessment for individual patients, rather than simply providing population-based approaches.

The 2013 ACC/AHA guidelines eliminated low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C)^a goals of therapy and replaced them with the concept of 4 “statin benefit groups”—that is, patient populations for which clear evidence supports the role of statin therapy.⁴ In the 2018 guideline, statin benefit groups have been maintained, although without explicit use of this term.¹

Primary prevention. Although no major changes in statin indications are made for patients with (1) established ASCVD (ie, for secondary prevention), (2) diabetes mellitus (DM) and who are 40 to 75 years of age, or (3) a primary LDL-C elevation ≥ 190 mg/dL, significant changes were made for primary prevention patients ages 40 to 75 years.¹ ASCVD risk calculation using the 2013 pooled cohort equations (PCE) is still recommended⁴; however, risk estimation is refined by the use of specific so-called risk-enhancing factors (TABLE 2¹). In cases in which the risk decision remains uncertain, obtaining the coronary artery calcium (CAC) score (which we’ll describe shortly) using specialized computed tomography (CT) is advised to facilitate the shared physician–patient decision-making process.¹

LDL-C and non-HDL-C thresholds. Although LDL-C and non-HDL-C goals are not overtly brought back from the 2002 National Cholesterol Education Program/Adult Treatment Panel guidelines,⁶ the new guideline does introduce LDL-C and non-HDL-C thresholds—levels at which adding nonstatin therapy can be considered, in contrast to previous goals to which therapy was titrated. Definitions of statin intensity remain the same: Moderate-intensity statin therapy is expected to reduce the LDL-C level by 30% to 50%; high-intensity statin therapy, by ≥ 50%.¹ The intensity of statin therapy has been de-escalated in the intermediate-risk group, where previous guidelines advised high-intensity statin therapy,⁴ and replaced with moderate-intensity statin therapy (similar to 2016 US Preventive Services Task Force [USPSTF] recommendations⁷).

[polldaddy:10312157]

Continue to: Fasting vs nonfasting lipid profiles

Fasting vs nonfasting lipid profiles. In contrast to previous guidelines,^2,8 which used fasting lipid profiles, nonfasting lipid profiles are now recommended for establishing a baseline LDL-C level and for ASCVD risk estimation for most patients—as long as the triglycerides (TG) level is < 400 mg/dL. When the calculated LDL-C level is < 70 mg/dL using the standard Friedewald formula, obtaining a direct LDL-C or a modified LDL-C estimate⁹ is deemed reasonable to improve accuracy. (The modified LDL-C can be estimated using The Johns Hopkins Hospital’s free “LDL Cholesterol Calculator” [www.hopkinsmedicine.org/apps/all-apps/ldl-cholesterol-calculator]).

A fasting lipid profile is still preferred for patients who have a family history of a lipid disorder. The definition of hypertriglyceridemia has been revised from a fasting TG level ≥ 150 mg/dL to a nonfasting or fasting TG level ≥ 175 mg/dL.¹

Nonstatin add-on therapy. The new guideline supports the addition of nonstatin therapies to maximally tolerated statin therapy in patients who have established ASCVD or a primary LDL-C elevation ≥ 190 mg/dL when (1) the LDL-C level has not been reduced by the expected percentage (≥ 50% for high-intensity statin therapy) or (2) explicit LDL-C level thresholds have been met.¹

Although measurement of the coronary artery calcium score by CT is generally not covered by insurance, its cost ($50-$450) nationwide makes it accessible.

The principal 2 groups of recommended nonstatins for which there is randomized, controlled trial evidence of cardiovascular benefit are (1) the cholesterol-absorbing agent ezetimibe¹⁰ and (2) the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors evolocumab¹¹ and alirocumab.¹²

AAFP’s guarded positions on the 2013 and 2018 guidelines

The American Academy of Family Physicians (AAFP) welcomed the patient-centered and outcome-oriented aspects of the 2013 ACC/AHA guidelines, endorsing them with 3 qualifications.¹³

1. Many of the recommendations were based on expert opinion, not rigorous research results—in particular, not on the findings of randomized controlled trials (although key points are based on high-quality evidence).
2. There were conflicts of interest disclosed for 15 members of the guidelines panel, including a vice chair.
3. Validation of the PCE risk estimation tool was lacking.

Continue to: AAFP announced...

AAFP announced in March that it does not endorse the 2018 AHA/ACC guideline, asserting that (1) only a small portion of the recommendations, primarily focused on the addition of nonstatin therapy, were addressed by an independent systematic review and (2) many of the guideline recommendations are based on low-quality or insufficient evidence. AAFP nevertheless bestowed an “affirmation of value” designation on the guideline—meaning that it provides some benefit for family physicians’ practice without fulfilling all criteria for full endorsement.¹⁴

Detailed recommendations from the 2018 guideline

Lifestyle modification

When talking about ASCVD risk with patients, it is important to review current lifestyle habits (eg, diet, physical activity, weight or body mass index, and tobacco use). Subsequent to that conversation, a healthy lifestyle should be endorsed and relevant advice provided. In addition, patient-directed materials (eg, ACC’s CardioSmart [www.cardiosmart.org]; AHA’s Life’s Simple 7 [www.heart.org/en/professional/workplace-health/lifes-simple-7]; and the National Lipid Association’s Patient Tear Sheets [www.lipid.org/practicetools/tools/tearsheets] and Clinicians’ Lifestyle Modification Toolbox [www.lipid.org/CLMT]) and referrals (eg, to cardiac rehabilitation, a dietitian, a smoking-cessation program) should be provided.¹

Primary prevention of ASCVD

Risk assessment for primary prevention is now approached as a process, rather than the simple risk calculation used in the 2013 ACC/AHA guidelines.² Assessment involves risk estimation followed by risk personalization, which, in some cases, is followed by risk reclassification using CAC scoring.¹

Patients are classified into 1 of 4 risk groups, based on the PCE¹:

• low (< 5%)
• borderline (5%-7.5%)
• intermediate (7.5%-19.9%)
• high (≥ 20%).

However, the PCE-based risk score is a population-based tool, which might not reflect the actual risk of individual patients. In some populations, PCE underestimates ASCVD risk; in others, it overestimates risk. A central tenet of the new guideline is personalization of risk, taking into account the unique circumstances of each patient. Moreover, the new guideline provides guidance on how to interpret the PCE risk score for several different ethnic and racial groups.¹

Continue to: Medical therapy

Medical therapy. The decision to start lipid-lowering therapy should be made after a physician–patient discussion that considers costs of therapy as well as patient preferences and values in the context of shared decision-making. Discussion should include a review of major risk factors (eg, cigarette smoking, elevated blood pressure, and the LDL-C level), the PCE risk score, the presence of risk-enhancing factors (TABLE 2¹), potential benefits of lifestyle changes and statin therapy, and the potential for adverse drug effects and drug–drug interactions.¹

If the estimated ASCVD risk is 7.5%-19.9%, starting moderate-intensity statin therapy is recommended. Risk-enhancing factors favor initiation of statin therapy, even in patients at borderline risk (5%-7.5%). If risk is uncertain, the CAC score can be used to facilitate shared decision-making.¹ The use of CAC is in agreement with the USPSTF statement that CAC can moderately improve discrimination and reclassification, but has an unclear effect on downstream health care utilization.¹⁵ Importantly, CAC should not be measured routinely in patients already taking a statin because its primary role is to facilitate shared decision-making regarding initiation of statin therapy.¹⁶

If the 10-year ASCVD risk is ≥ 20%, high-intensity statin therapy is advised, without need to obtain the CAC score. If high-intensity statin therapy is advisable but not acceptable to, or tolerated by, the patient, it might be reasonable to add a nonstatin drug (ezetimibe or a bile-acid sequestrant) to moderate-intensity statin therapy.¹

Risk-enhancing factors (TABLE 2¹) apply to intermediate- and borderline-risk patients. Importantly, these factors include membership in specific ethnic groups, conditions specific to females, and male–female distinctions in risk. Risk-enhancing factors also incorporate biomarkers that are often measured by lipid specialists, such as lipoprotein(a) (Lp[a]) and apolipoprotein B (ApoB).¹

Lp(a) is an atherogenic particle, akin to an LDL particle, that consists of a molecule of apolipoprotein (a) (a nonfunctional mimic of a portion of plasminogen) covalently bound to ApoB, like the one found on the LDL particle. Lp(a) is proportionally associated with an increased risk for ASCVD and aortic stenosis at a level > 50 mg/dL.¹⁷ A family history of premature ASCVD is a relative indication for measuring Lp(a).¹

Continue to: When and why to measure CAC

When and why to measure CAC

If the decision to initiate statin therapy is still uncertain after risk estimation and personalization, or when a patient is undecided about committing to lifelong lipid-lowering therapy, the new guideline recommends obtaining a CAC score to inform the shared decision-making process.^1,18 Measurement of CAC is obtained by noncontrast, electrocardiographic-gated CT that can be performed in 10 to 15 minutes, requiring approximately 1 millisievert of radiation (equivalent of the approximate dose absorbed during 2 mammograms). Although measurement of the CAC score is generally not covered by insurance, its cost ($50-$450) nationwide makes it accessible.¹⁹

The guideline endorses reverse cascade screening for detection of familial hypercholesterolemia in family members of children and adolescents who have severe hypercholesterolemia.

CAC measures the presence (or absence) of subclinical atherosclerosis by detecting calcified plaque in coronary arteries. The absolute CAC score is expressed in Agatston units; an age–gender population percentile is also provided. Keep in mind that the presence of any CAC (ie, a score > 0) is abnormal and demonstrates the presence of subclinical coronary artery disease. The prevalence of CAC > 0 increases with age, but a significant percentage of older people have a CAC score = 0. When CAC > 0, additional information is provided by the distribution of plaque burden among the different coronary arteries.²⁰

Among intermediate-risk patients, 50% have CAC = 0 and, therefore, a very low event rate over the ensuing 10 years, which allows statin therapy to be safely deferred unless certain risk factors are present (eg, family history, smoking, DM).^1,18 It is reasonable to repeat CAC testing in 5 to 10 years to assess whether subclinical atherosclerosis has developed. The 2018 guideline emphasizes that, when the CAC score is > 0 but < 100 Agatston units, statin therapy is favored, especially in patients > 55 years of age; when the CAC score is ≥ 100 Agatston units or at the ≥ 75th percentile, statin therapy is indicated regardless of age.¹

Patients who might benefit from knowing their CAC score include those who are:

• reluctant to initiate statin therapy but who want to understand their risk and potential for benefit more precisely
• concerned about the need to reinstitute statin therapy after discontinuing it because of statin-associated adverse effects
• older (men, 55-80 years; women, 60-80 years) who have a low burden of risk factors and who question whether they would benefit from statin therapy
• middle-aged (40-55 years) and who have a PCE-calculated risk of 5% to < 7.5% for ASCVD and factors that increase their risk for ASCVD, even though they are in a borderline-risk group.¹

Primary prevention in special populations

Older patients. In adults ≥ 75 years who have an LDL-C level 70 to 189 mg/dL, initiating a moderate-intensity statin might be reasonable; however, it might also be reasonable to stop treatment in this population when physical or cognitive decline, multiple morbidities, frailty, or reduced life expectancy limits the potential benefit of statin therapy. It might be reasonable to use the CAC score in adults 76 to 80 years of age who have an LDL-C level of 70 to 189 mg/dL to reclassify those whose CAC score = 0, so that they can avoid statin therapy.¹

Continue to: Children and adolescents

Children and adolescents. In alignment with current pediatric guidelines,²¹ but in contrast to USPSTF reccomendations,²² the 2018 ACC/AHA guideline endorses universal lipid screening for pediatric patients (see TABLE W1^1,21,22). It is reasonable to obtain a fasting lipid profile or nonfasting non-HDL-C in all children and adolescents who have neither cardiovascular risk factors nor a family history of early cardiovascular disease to detect moderate-to-severe lipid abnormalities. Screening should be done once at 9 to 11 years of age and again at 17 to 21 years.¹

A screening test as early as 2 years of age to detect familial hypercholesterolemia (FH) is reasonable when a family history of either early CVD or significant hypercholesterolemia is present. The guideline endorses reverse cascade screening for detection of FH in family members of children and adolescents who have severe hypercholesterolemia.¹

Risk-enhancing factors favor initiation of statin therapy, even in patients at borderline risk.

In children and adolescents with a lipid abnormality, especially when associated with the metabolic syndrome, lifestyle counseling is beneficial for lowering the LDL-C level. In children and adolescents ≥ 10 years of age with (1) an LDL-C level persistently ≥ 190 mg/dL or (2) an LDL level ≥ 160 mg/dL plus a clinical presentation consistent with FH, it is reasonable to initiate statin therapy if they do not respond adequately to 3 to 6 months of lifestyle therapy.¹

Ethnicity as a risk-modifying factor. The PCE distinguishes between US adults of European ancestry and African ancestry, but no other ethnic groups are distinguished.⁴ The new guideline advocates for the use of PCE in other populations; however, it states that, for clinical decision-making purposes, it is reasonable, in adults of different races and ethnicities, for the physician to review racial and ethnic features that can influence ASCVD risk to allow adjustment of the choice of statin or intensity of treatment. Specifically, South Asian ancestry is now treated as a risk-enhancing factor, given the high prevalence of premature and extensive ASCVD in this patient population.¹

Concerns specific to women. Considering conditions specific to women as potential risk-enhancing factors is advised when discussing lifestyle intervention and the potential for benefit from statin therapy—in particular, (1) in the setting of premature menopause (< 40 years) and (2) when there is a history of a pregnancy-associated disorder (eg, hypertension, preeclampsia, gestational DM, a small-for-gestational-age infant, and preterm delivery). If the decision is made to initiate statin therapy in women of childbearing age who are sexually active, there is a guideline mandate to counsel patients on using reliable contraception. When pregnancy is planned, statin therapy should be discontinued 1 to 2 months before pregnancy is attempted; when pregnancy occurs while a patient is taking a statin, therapy should be stopped as soon as the pregnancy is discovered.¹

Continue to: Adults with chronic kidney disease

Adults with chronic kidney disease. Chronic kidney disease that is not treated with dialysis or kidney transplantation is considered a risk-enhancing factor; initiation of a moderate-intensity statin or a moderate-intensity statin plus ezetimibe can be useful in patients with chronic kidney disease who are 40 to 75 years of age and have an LDL-C level of 70 to 189 mg/dL and a PCE-calculated risk ≥ 7.5%. In adults with advanced kidney disease that requires dialysis who are already taking a statin, it may be reasonable to continue the statin; however, initiation of a statin in adults with advanced kidney disease who require dialysis is not recommended because of an apparent lack of benefit.¹

Adults with a chronic inflammatory disorder or human immunodeficiency virus infection. Any of these conditions are treated as risk-enhancing factors; in a risk discussion with affected patients, therefore, moderate-intensity statin therapy or high-intensity statin therapy is favored for those 40 to 75 years of age who have an LDL-C level of 70 to 189 mg/dL and PCE-calculated risk ≥ 7.5%. A fasting lipid profile and assessment of ASCVD risk factors for these patients can be useful (1) as a guide to the potential benefit of statin therapy and (2) for monitoring or adjusting lipid-lowering drug therapy before, and 4 to 12 weeks after, starting inflammatory disease-modifying therapy or antiretroviral therapy.

In adults with rheumatoid arthritis who undergo ASCVD risk assessment with a lipid profile, it can be useful to recheck lipid values and other major ASCVD risk factors 2 to 4 months after the inflammatory disease has been controlled.¹

Primary hypercholesterolemia

The diagnosis and management of heterozygous or homozygous familial hypercholesterolemia (HeFH or HoFH) is beyond the scope of the 2018 ACC/AHA cholesterol guidelines; instead, the 2015 AHA Scientific Statement, “The Agenda for Familial Hypercholesterolemia,” provides a contemporary review of these topics.²³ However, the 2018 cholesterol guideline does acknowledge that an LDL-C level ≥ 190 mg/dL often corresponds to primary (ie, genetic) hypercholesterolemia.

In patients 20 to 75 years of age who have a primary elevation of LDL-C level ≥ 190 mg/dL, the guideline recommends initiation of high-intensity statin therapy without calculating ASCVD risk using the PCE. If a > 50% LDL-C reduction is not achieved, or if the LDL-C level on maximally tolerated statin therapy remains ≥ 100 mg/dL, adding ezetimibe is considered reasonable. If there is < 50% reduction in the LDL-C level while taking maximally tolerated statin and ezetimibe therapy, adding a bile-acid sequestrant can be considered, as long as the TG level is not > 300 mg/dL (ie, bile-acid sequestrants can elevate the TG level significantly).

Continue to: In patients 30 to 75 years of age...

In patients 30 to 75 years of age who have a diagnosis of HeFH and an LDL-C level ≥ 100 mg/dL while taking maximally tolerated statin and ezetimibe therapy, the addition of a PCSK9 inhibitor can be considered. Regardless of whether there is a diagnosis of HeFH, addition of a PCSK9 inhibitor can be considered in patients 40 to 75 years of age who have a baseline LDL-C level ≥ 220 mg/dL and who achieve an on-treatment LDL-C level ≥ 130 mg/dL while receiving maximally tolerated statin therapy and ezetimibe.¹

Diabetes mellitus

In patients with DM who are 40 to 75 years of age, moderate-intensity statin therapy is recommended without calculating the 10-year ASCVD risk. When the LDL-C level is 70 to 189 mg/dL, however, it is reasonable to use the PCE to assess 10-year ASCVD risk to facilitate risk stratification.

In patients 20 to 75 years of age who have a primary elevation of LDL-C level ≥ 190 mg/dL, the guideline recommends initiation of high-intensity statin therapy without calculating ASCVD risk.

In patients with DM who are at higher risk, especially those who have multiple risk factors or are 50 to 75 years of age, it is reasonable to use a high-intensity statin to reduce the LDL-C level by ≥ 50 %. In adults > 75 years of age with DM who are already on statin therapy, it is reasonable to continue statin therapy; for those that age who are not on statin therapy, it might be reasonable to initiate statin therapy after a physician–patient discussion of potential benefits and risks.

In adults with DM and PCE-calculated risk ≥ 20%, it might be reasonable to add ezetimibe to maximally tolerated statin therapy to reduce the LDL-C level by ≥ 50%. In adults 20 to 39 years of age with DM of long duration (≥ 10 years of type 2 DM, ≥ 20 years of type 1 DM), albuminuria (≥ 30 μg of albumin/mg creatinine), estimated glomerular filtration rate < 60 mL/min/1.73 m², retinopathy, neuropathy, or ankle-brachial index < 0.9, it might be reasonable to initiate statin therapy.¹

Secondary prevention

Presence of clinical ASCVD. In patients with clinical ASCVD who are ≤ 75 years of age, high-intensity statin therapy should be initiated or continued, with the aim of achieving ≥ 50% reduction in the LDL-C level. When high-intensity statin therapy is contraindicated or if a patient experiences statin-associated adverse effects, moderate-intensity statin therapy should be initiated or continued with the aim of achieving a 30% to 49% reduction in the LDL-C level.

Continue to: In patients...

In patients > 75 years of age with clinical ASCVD, it is reasonable to initiate or continue moderate- or high-intensity statin therapy after evaluation of the potential for ASCVD risk reduction, adverse effects, and drug–drug interactions, as well as patient frailty and patient preference.¹

Very high risk. In patients at very high risk (this includes a history of multiple major ASCVD events or 1 major ASCVD event plus multiple high-risk conditions), maximally tolerated LDL-C-lowering therapy should include maximally tolerated statin therapy and ezetimibe before considering a PCSK9 inhibitor. An LDL-C level ≥ 70 mg/dL or a non-HDL-C level ≥ 100 mg/dL is considered a reasonable threshold for adding a PCSK9 inhibitor to background lipid-lowering therapy¹ (TABLE 3¹).

Heart failure. In patients with heart failure who have (1) a reduced ejection fraction attributable to ischemic heart disease, (2) a reasonable life expectancy (3-5 years), and (3) are not already on a statin because of ASCVD, consider initiating moderate-intensity statin therapy to reduce the risk for an ASCVD event.¹

Reduction of elevated triglycerides

The guideline defines moderate hypertriglyceridemia as a nonfasting or fasting TG level of 175 to 499 mg/dL. Such a finding is considered a risk-enhancing factor and is 1 of 5 components of the metabolic syndrome. Three independent measurements are advised to diagnose primary moderate hypertriglyceridemia. Severe hypertriglyceridemia is diagnosed when the fasting TG level is ≥ 500 mg/dL.¹

In moderate hypertriglyceridemia, most TGs are carried in very-low-density lipoprotein particles; in severe hypertriglyceridemia, on the other hand, chylomicrons predominate, raising the risk for pancreatitis. In adults with severe hypertriglyceridemia, therefore—especially when the fasting TG level is ≥ 1000 mg/dL—it is reasonable to identify and address other causes of hypertriglyceridemia. If TGs are persistently elevated or increasing, levels should be reduced to prevent acute pancreatitis with a very low-fat diet and by avoiding refined carbohydrates and alcohol; consuming omega-3 fatty acids; and, if necessary, taking a fibrate.¹

Continue to: In adults...

In adults ≥ 20 years of age with moderate hypertriglyceridemia, lifestyle factors (eg, obesity, metabolic syndrome), secondary factors (eg, DM, chronic liver or kidney disease, nephrotic syndrome, hypothyroidism), and medications that increase the TG level need to be addressed first. In adults 40 to 75 years of age with moderate or severe hypertriglyceridemia and a PCE-calculated ASCVD risk ≥ 7.5%, it is reasonable to reevaluate risk after lifestyle and secondary factors are addressed and to consider a persistently elevated TG level as a factor favoring initiation or intensification of statin therapy. In adults 40 to 75 years of age with severe hypertriglyceridemia and ASCVD risk ≥ 7.5%, it is reasonable to address reversible causes of a high TG level and to initiate statin therapy.¹

Other considerations in cholesterol management

Tools to assess adherence

The response to lifestyle and statin therapy should be evaluated by the percentage reduction in the LDL-C level compared with baseline, not by assessment of the absolute LDL-C level. When seeing a patient whose treatment is ongoing, a baseline level can be estimated using a desktop LDL-calculator app.

When pregnancy is planned, statin therapy should be discontinued 1-2 months before pregnancy is attempted.

Adherence and percentage response to LDL-C–lowering medications and lifestyle changes should be evaluated with repeat lipid measurement 4 to 12 weeks after either a statin is initiated or the dosage is adjusted, and repeated every 3 to 12 months as needed. In patients with established ASCVD who are at very high risk, triggers for adding nonstatin therapy are defined by a threshold LDL-C level ≥ 70 mg/dL on maximal statin therapy.¹

Interventions focused on improving adherence to prescribed therapy are recommended for management of adults with an elevated cholesterol level. These interventions include telephone reminders, calendar reminders, integrated multidisciplinary educational activities, and pharmacist-led interventions, such as simplification of the medication regimen to once-daily dosing.¹

Statin safety and associated adverse effects

A physician–patient risk discussion is recommended before initiating statin therapy to review net clinical benefit, during which the 2 parties weigh the potential for ASCVD risk reduction against the potential for statin-associated adverse effects, statin–drug interactions, and safety, with the physician emphasizing that adverse effects can be addressed successfully.

Continue to: Statins are one of...

Statins are one of the safest classes of medication, with an excellent risk-benefit ratio. However, there are myriad confusing media reports regarding potential adverse effects and safety of the statin class—reports that often lead patients to discontinue or refuse statins.

Statin-associated adverse effects include the common statin-associated muscle symptoms (SAMS), new-onset DM, cognitive effects, and hepatic injury. The frequency of new-onset DM depends on the population exposed to statins, with a higher incidence of new-onset DM found in patients who are already predisposed, such as those with obesity, prediabetes, and metabolic syndrome. Cognitive effects are rare and difficult to interpret; they were not reported in the large statin mega-trials but have been described in case reports. Significant transaminase elevations > 3 times the upper limit of normal are infrequent; hepatic failure with statins is extremely rare and found at the same incidence in the general population.¹

SAMS include (in order of decreasing prevalence)²⁴:

• myalgias with a normal creatine kinase (CK) level
• conditions such as myositis or myopathy (elevated CK level)
• rhabdomyolysis (CK level > 10 times the upper limit of normal, plus renal injury)
• extremely rare statin-associated autoimmune myopathy, with detectable 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase antibodies.

In patients with SAMS, thorough assessment of symptoms is recommended, in addition to evaluation for nonstatin causes and predisposing factors. Identification of potential SAMS-predisposing factors is recommended before initiation of treatment, including demographics (eg, East-Asian ancestry), comorbid conditions (eg, hypothyroidism and vitamin D deficiency), and use of medications adversely affecting statin metabolism (eg, cyclosporine).

In patients with statin-associated adverse effects that are not severe, it is recommended to reassess and rechallenge to achieve a maximal lowering of the LDL-C level by a modified dosing regimen or an alternate statin or by combining a statin with nonstatin therapy. In patients with increased risk for DM or new-onset DM, it is recommended to continue statin therapy.

Continue to: Routine CK and liver function testing...

Routine CK and liver function testing is not useful in patients treated with statins; however, it is recommended that CK be measured in patients with severe SAMS or objective muscle weakness, or both, and to measure liver function if symptoms suggest hepatotoxicity. In patients at increased risk for ASCVD who have chronic, stable liver disease (including non-alcoholic fatty liver disease), it is reasonable, when appropriately indicated, to use statins after obtaining baseline measurements and determining a schedule of monitoring and safety checks.

Implementing the 2018 guideline in practice might remain a challenge to clinicians who are inexperienced in ordering lipid markers such as Lp(a) and interpreting the CAC score.

In patients at increased risk for ASCVD who have severe or recurrent SAMS after appropriate statin rechallenge, it is reasonable to use nonstatin therapy that is likely to provide net clinical benefit. The guideline does not recommend routine use of coenzyme Q10 supplementation for the treatment or prevention of SAMS.¹

Guideline criticism

Guideline development is challenging on multiple levels, including balancing perspectives from multiple stakeholders. Nevertheless, the 2018 AHA/ACC cholesterol guideline builds nicely on progress made since its 2013 predecessor was released.⁴ This document was developed with the participation of representatives from 10 professional societies in addition to the ACC and AHA—notably, the National Lipid Association and American Society for Preventive Cardiology.¹

To refine risk estimation and facilitate shared decision-making, the new guideline introduced so-called risk-enhancing factors and use of the CAC.¹ However, some potential risk-enhancing factors were left out: erectile dysfunction, for example, often a marker of increased cardiovascular risk in men < 50 years of age.²⁵ In addition, although pretreatment ApoB was introduced as a risk-enhancing factor,¹ no recommendation is given to measure ApoB after initiation of therapy for evaluation of residual cardiovascular risk, as endorsed in other guidelines.^26,27

Moreover, the guideline does not include the “extreme risk” category in the guideline developed by the American Association of Clinical Endocrinologists (AACE).²⁸ Although the 2018 AHA/ACC guideline introduces < 70 mg/dL and < 100 mg/dL LDL-C thresholds,¹ the < 55 mg/dL LDL-C threshold used for patients in the AACE/American College of Endocrinology extreme-risk category is not mentioned.²⁶ This omission might leave patients who are at extreme ASCVD risk without optimal lipid-lowering therapy. Similarly, the guideline does not elaborate on the diagnosis and treatment of HoFH and HeFH.¹ The age cutoff of 30 years for the recommendation to consider PCSK9 inhibitors in patients with HeFH appears arbitrary and excludes younger FH patients who have an extreme LDL-C elevation from potentially important therapy.²³

Continue to: Guidelines are dynamic instruments...

Guidelines are dynamic instruments that require constant updating, given the production of new evidence. In fact, the results of the Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial (REDUCE-IT) were presented at the same meeting at which this guideline was unveiled.²⁹ REDUCE-IT demonstrated an astonishing highly significant 25% reduction in the composite primary major adverse cardiovascular event outcome in patients with an LDL-C level of 44 to 100 mg/dL on statin therapy, who had a TG level of 135 to 499 mg/dL and had been treated for a median of 4.9 years with 4 g of pure eicosapentaenoic acid.

In addition, the guideline’s value statements, which address the need to consider the cost of drugs in determining most appropriate treatment, are no longer accurate because the price of PCSK9 inhibitors has dropped by more than half since the guideline was issued.³⁰

An upward climb to clinical payoff

Even after close study of the 2018 AHA/ACC cholesterol guideline, implementing it in practice might remain a challenge to clinicians who are inexperienced in ordering lipid markers such as Lp(a) and interpreting the CAC score. Moreover, initiating and monitoring nonstatin therapies will be a demanding task—especially with PCSK9 inhibitors, which present access difficulties because they are relatively expensive (even after the recent price cut). That’s why, when there is doubt in the mind of the physician or other provider, we will likely see more referrals to specialists in lipid management and ASCVD risk estimation to optimize preventive therapy.³¹

CORRESPONDENCE
Cezary Wójcik, MD, PhD, FNLA, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239; [email protected]

A new cholesterol guideline¹ builds on the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol guidelines,² which were a major paradigm shift in the evaluation and management of blood cholesterol levels and risk for atherosclerotic cardiovascular disease (ASCVD). The work was presented (and simultaneously published) on November 10, 2018, at the annual AHA Scientific Sessions in Chicago. Full text,¹ an executive summary,³ and accompanying systematic review of evidence⁴ are available online.

The 2018 AHA/ACC cholesterol guideline represents a step forward in ASCVD prevention—especially in primary prevention, where it provides guidance for risk refinement and personalization. In this article, we mine the details of what has changed and what is new in this guideline so that you can prepare to adopt the recommendations in your practice.

IMAGE: © JOE GORMAN

2013 and 2018 guidelines: Similarities, differences

As in earlier iterations, the 2018 guideline emphasizes healthy lifestyle across the life-course as the basis of ASCVD prevention—as elaborated in the 2013 AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk.⁵ In contrast to the 2013 guidelines,² the 2018 guideline is more comprehensive and more personalized, focusing on risk assessment for individual patients, rather than simply providing population-based approaches. Moreover, the guideline isn’t limited to adults: It makes recommendations pertaining to children and adolescents.¹

TABLE 1^1,2 compares the most important differences between the 2013 and 2018 guidelines.

In contrast to the 2013 guidelines, the 2018 guideline is more comprehensive and more personalized, focusing on risk assessment for individual patients, rather than simply providing population-based approaches.

The 2013 ACC/AHA guidelines eliminated low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C)^a goals of therapy and replaced them with the concept of 4 “statin benefit groups”—that is, patient populations for which clear evidence supports the role of statin therapy.⁴ In the 2018 guideline, statin benefit groups have been maintained, although without explicit use of this term.¹

Primary prevention. Although no major changes in statin indications are made for patients with (1) established ASCVD (ie, for secondary prevention), (2) diabetes mellitus (DM) and who are 40 to 75 years of age, or (3) a primary LDL-C elevation ≥ 190 mg/dL, significant changes were made for primary prevention patients ages 40 to 75 years.¹ ASCVD risk calculation using the 2013 pooled cohort equations (PCE) is still recommended⁴; however, risk estimation is refined by the use of specific so-called risk-enhancing factors (TABLE 2¹). In cases in which the risk decision remains uncertain, obtaining the coronary artery calcium (CAC) score (which we’ll describe shortly) using specialized computed tomography (CT) is advised to facilitate the shared physician–patient decision-making process.¹

LDL-C and non-HDL-C thresholds. Although LDL-C and non-HDL-C goals are not overtly brought back from the 2002 National Cholesterol Education Program/Adult Treatment Panel guidelines,⁶ the new guideline does introduce LDL-C and non-HDL-C thresholds—levels at which adding nonstatin therapy can be considered, in contrast to previous goals to which therapy was titrated. Definitions of statin intensity remain the same: Moderate-intensity statin therapy is expected to reduce the LDL-C level by 30% to 50%; high-intensity statin therapy, by ≥ 50%.¹ The intensity of statin therapy has been de-escalated in the intermediate-risk group, where previous guidelines advised high-intensity statin therapy,⁴ and replaced with moderate-intensity statin therapy (similar to 2016 US Preventive Services Task Force [USPSTF] recommendations⁷).

[polldaddy:10312157]

Continue to: Fasting vs nonfasting lipid profiles

Fasting vs nonfasting lipid profiles. In contrast to previous guidelines,^2,8 which used fasting lipid profiles, nonfasting lipid profiles are now recommended for establishing a baseline LDL-C level and for ASCVD risk estimation for most patients—as long as the triglycerides (TG) level is < 400 mg/dL. When the calculated LDL-C level is < 70 mg/dL using the standard Friedewald formula, obtaining a direct LDL-C or a modified LDL-C estimate⁹ is deemed reasonable to improve accuracy. (The modified LDL-C can be estimated using The Johns Hopkins Hospital’s free “LDL Cholesterol Calculator” [www.hopkinsmedicine.org/apps/all-apps/ldl-cholesterol-calculator]).

A fasting lipid profile is still preferred for patients who have a family history of a lipid disorder. The definition of hypertriglyceridemia has been revised from a fasting TG level ≥ 150 mg/dL to a nonfasting or fasting TG level ≥ 175 mg/dL.¹

Nonstatin add-on therapy. The new guideline supports the addition of nonstatin therapies to maximally tolerated statin therapy in patients who have established ASCVD or a primary LDL-C elevation ≥ 190 mg/dL when (1) the LDL-C level has not been reduced by the expected percentage (≥ 50% for high-intensity statin therapy) or (2) explicit LDL-C level thresholds have been met.¹

Although measurement of the coronary artery calcium score by CT is generally not covered by insurance, its cost ($50-$450) nationwide makes it accessible.

The principal 2 groups of recommended nonstatins for which there is randomized, controlled trial evidence of cardiovascular benefit are (1) the cholesterol-absorbing agent ezetimibe¹⁰ and (2) the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors evolocumab¹¹ and alirocumab.¹²

AAFP’s guarded positions on the 2013 and 2018 guidelines

The American Academy of Family Physicians (AAFP) welcomed the patient-centered and outcome-oriented aspects of the 2013 ACC/AHA guidelines, endorsing them with 3 qualifications.¹³

1. Many of the recommendations were based on expert opinion, not rigorous research results—in particular, not on the findings of randomized controlled trials (although key points are based on high-quality evidence).
2. There were conflicts of interest disclosed for 15 members of the guidelines panel, including a vice chair.
3. Validation of the PCE risk estimation tool was lacking.

Continue to: AAFP announced...

AAFP announced in March that it does not endorse the 2018 AHA/ACC guideline, asserting that (1) only a small portion of the recommendations, primarily focused on the addition of nonstatin therapy, were addressed by an independent systematic review and (2) many of the guideline recommendations are based on low-quality or insufficient evidence. AAFP nevertheless bestowed an “affirmation of value” designation on the guideline—meaning that it provides some benefit for family physicians’ practice without fulfilling all criteria for full endorsement.¹⁴

Detailed recommendations from the 2018 guideline

Lifestyle modification

When talking about ASCVD risk with patients, it is important to review current lifestyle habits (eg, diet, physical activity, weight or body mass index, and tobacco use). Subsequent to that conversation, a healthy lifestyle should be endorsed and relevant advice provided. In addition, patient-directed materials (eg, ACC’s CardioSmart [www.cardiosmart.org]; AHA’s Life’s Simple 7 [www.heart.org/en/professional/workplace-health/lifes-simple-7]; and the National Lipid Association’s Patient Tear Sheets [www.lipid.org/practicetools/tools/tearsheets] and Clinicians’ Lifestyle Modification Toolbox [www.lipid.org/CLMT]) and referrals (eg, to cardiac rehabilitation, a dietitian, a smoking-cessation program) should be provided.¹

Primary prevention of ASCVD

Risk assessment for primary prevention is now approached as a process, rather than the simple risk calculation used in the 2013 ACC/AHA guidelines.² Assessment involves risk estimation followed by risk personalization, which, in some cases, is followed by risk reclassification using CAC scoring.¹

Patients are classified into 1 of 4 risk groups, based on the PCE¹:

• low (< 5%)
• borderline (5%-7.5%)
• intermediate (7.5%-19.9%)
• high (≥ 20%).

However, the PCE-based risk score is a population-based tool, which might not reflect the actual risk of individual patients. In some populations, PCE underestimates ASCVD risk; in others, it overestimates risk. A central tenet of the new guideline is personalization of risk, taking into account the unique circumstances of each patient. Moreover, the new guideline provides guidance on how to interpret the PCE risk score for several different ethnic and racial groups.¹

Continue to: Medical therapy

Medical therapy. The decision to start lipid-lowering therapy should be made after a physician–patient discussion that considers costs of therapy as well as patient preferences and values in the context of shared decision-making. Discussion should include a review of major risk factors (eg, cigarette smoking, elevated blood pressure, and the LDL-C level), the PCE risk score, the presence of risk-enhancing factors (TABLE 2¹), potential benefits of lifestyle changes and statin therapy, and the potential for adverse drug effects and drug–drug interactions.¹

If the estimated ASCVD risk is 7.5%-19.9%, starting moderate-intensity statin therapy is recommended. Risk-enhancing factors favor initiation of statin therapy, even in patients at borderline risk (5%-7.5%). If risk is uncertain, the CAC score can be used to facilitate shared decision-making.¹ The use of CAC is in agreement with the USPSTF statement that CAC can moderately improve discrimination and reclassification, but has an unclear effect on downstream health care utilization.¹⁵ Importantly, CAC should not be measured routinely in patients already taking a statin because its primary role is to facilitate shared decision-making regarding initiation of statin therapy.¹⁶

If the 10-year ASCVD risk is ≥ 20%, high-intensity statin therapy is advised, without need to obtain the CAC score. If high-intensity statin therapy is advisable but not acceptable to, or tolerated by, the patient, it might be reasonable to add a nonstatin drug (ezetimibe or a bile-acid sequestrant) to moderate-intensity statin therapy.¹

Risk-enhancing factors (TABLE 2¹) apply to intermediate- and borderline-risk patients. Importantly, these factors include membership in specific ethnic groups, conditions specific to females, and male–female distinctions in risk. Risk-enhancing factors also incorporate biomarkers that are often measured by lipid specialists, such as lipoprotein(a) (Lp[a]) and apolipoprotein B (ApoB).¹

Lp(a) is an atherogenic particle, akin to an LDL particle, that consists of a molecule of apolipoprotein (a) (a nonfunctional mimic of a portion of plasminogen) covalently bound to ApoB, like the one found on the LDL particle. Lp(a) is proportionally associated with an increased risk for ASCVD and aortic stenosis at a level > 50 mg/dL.¹⁷ A family history of premature ASCVD is a relative indication for measuring Lp(a).¹

Continue to: When and why to measure CAC

When and why to measure CAC

If the decision to initiate statin therapy is still uncertain after risk estimation and personalization, or when a patient is undecided about committing to lifelong lipid-lowering therapy, the new guideline recommends obtaining a CAC score to inform the shared decision-making process.^1,18 Measurement of CAC is obtained by noncontrast, electrocardiographic-gated CT that can be performed in 10 to 15 minutes, requiring approximately 1 millisievert of radiation (equivalent of the approximate dose absorbed during 2 mammograms). Although measurement of the CAC score is generally not covered by insurance, its cost ($50-$450) nationwide makes it accessible.¹⁹

The guideline endorses reverse cascade screening for detection of familial hypercholesterolemia in family members of children and adolescents who have severe hypercholesterolemia.

CAC measures the presence (or absence) of subclinical atherosclerosis by detecting calcified plaque in coronary arteries. The absolute CAC score is expressed in Agatston units; an age–gender population percentile is also provided. Keep in mind that the presence of any CAC (ie, a score > 0) is abnormal and demonstrates the presence of subclinical coronary artery disease. The prevalence of CAC > 0 increases with age, but a significant percentage of older people have a CAC score = 0. When CAC > 0, additional information is provided by the distribution of plaque burden among the different coronary arteries.²⁰

Among intermediate-risk patients, 50% have CAC = 0 and, therefore, a very low event rate over the ensuing 10 years, which allows statin therapy to be safely deferred unless certain risk factors are present (eg, family history, smoking, DM).^1,18 It is reasonable to repeat CAC testing in 5 to 10 years to assess whether subclinical atherosclerosis has developed. The 2018 guideline emphasizes that, when the CAC score is > 0 but < 100 Agatston units, statin therapy is favored, especially in patients > 55 years of age; when the CAC score is ≥ 100 Agatston units or at the ≥ 75th percentile, statin therapy is indicated regardless of age.¹

Patients who might benefit from knowing their CAC score include those who are:

• reluctant to initiate statin therapy but who want to understand their risk and potential for benefit more precisely
• concerned about the need to reinstitute statin therapy after discontinuing it because of statin-associated adverse effects
• older (men, 55-80 years; women, 60-80 years) who have a low burden of risk factors and who question whether they would benefit from statin therapy
• middle-aged (40-55 years) and who have a PCE-calculated risk of 5% to < 7.5% for ASCVD and factors that increase their risk for ASCVD, even though they are in a borderline-risk group.¹

Primary prevention in special populations

Older patients. In adults ≥ 75 years who have an LDL-C level 70 to 189 mg/dL, initiating a moderate-intensity statin might be reasonable; however, it might also be reasonable to stop treatment in this population when physical or cognitive decline, multiple morbidities, frailty, or reduced life expectancy limits the potential benefit of statin therapy. It might be reasonable to use the CAC score in adults 76 to 80 years of age who have an LDL-C level of 70 to 189 mg/dL to reclassify those whose CAC score = 0, so that they can avoid statin therapy.¹

Continue to: Children and adolescents

Children and adolescents. In alignment with current pediatric guidelines,²¹ but in contrast to USPSTF reccomendations,²² the 2018 ACC/AHA guideline endorses universal lipid screening for pediatric patients (see TABLE W1^1,21,22). It is reasonable to obtain a fasting lipid profile or nonfasting non-HDL-C in all children and adolescents who have neither cardiovascular risk factors nor a family history of early cardiovascular disease to detect moderate-to-severe lipid abnormalities. Screening should be done once at 9 to 11 years of age and again at 17 to 21 years.¹

A screening test as early as 2 years of age to detect familial hypercholesterolemia (FH) is reasonable when a family history of either early CVD or significant hypercholesterolemia is present. The guideline endorses reverse cascade screening for detection of FH in family members of children and adolescents who have severe hypercholesterolemia.¹

Risk-enhancing factors favor initiation of statin therapy, even in patients at borderline risk.

In children and adolescents with a lipid abnormality, especially when associated with the metabolic syndrome, lifestyle counseling is beneficial for lowering the LDL-C level. In children and adolescents ≥ 10 years of age with (1) an LDL-C level persistently ≥ 190 mg/dL or (2) an LDL level ≥ 160 mg/dL plus a clinical presentation consistent with FH, it is reasonable to initiate statin therapy if they do not respond adequately to 3 to 6 months of lifestyle therapy.¹

Ethnicity as a risk-modifying factor. The PCE distinguishes between US adults of European ancestry and African ancestry, but no other ethnic groups are distinguished.⁴ The new guideline advocates for the use of PCE in other populations; however, it states that, for clinical decision-making purposes, it is reasonable, in adults of different races and ethnicities, for the physician to review racial and ethnic features that can influence ASCVD risk to allow adjustment of the choice of statin or intensity of treatment. Specifically, South Asian ancestry is now treated as a risk-enhancing factor, given the high prevalence of premature and extensive ASCVD in this patient population.¹

Concerns specific to women. Considering conditions specific to women as potential risk-enhancing factors is advised when discussing lifestyle intervention and the potential for benefit from statin therapy—in particular, (1) in the setting of premature menopause (< 40 years) and (2) when there is a history of a pregnancy-associated disorder (eg, hypertension, preeclampsia, gestational DM, a small-for-gestational-age infant, and preterm delivery). If the decision is made to initiate statin therapy in women of childbearing age who are sexually active, there is a guideline mandate to counsel patients on using reliable contraception. When pregnancy is planned, statin therapy should be discontinued 1 to 2 months before pregnancy is attempted; when pregnancy occurs while a patient is taking a statin, therapy should be stopped as soon as the pregnancy is discovered.¹

Continue to: Adults with chronic kidney disease

Adults with chronic kidney disease. Chronic kidney disease that is not treated with dialysis or kidney transplantation is considered a risk-enhancing factor; initiation of a moderate-intensity statin or a moderate-intensity statin plus ezetimibe can be useful in patients with chronic kidney disease who are 40 to 75 years of age and have an LDL-C level of 70 to 189 mg/dL and a PCE-calculated risk ≥ 7.5%. In adults with advanced kidney disease that requires dialysis who are already taking a statin, it may be reasonable to continue the statin; however, initiation of a statin in adults with advanced kidney disease who require dialysis is not recommended because of an apparent lack of benefit.¹

Adults with a chronic inflammatory disorder or human immunodeficiency virus infection. Any of these conditions are treated as risk-enhancing factors; in a risk discussion with affected patients, therefore, moderate-intensity statin therapy or high-intensity statin therapy is favored for those 40 to 75 years of age who have an LDL-C level of 70 to 189 mg/dL and PCE-calculated risk ≥ 7.5%. A fasting lipid profile and assessment of ASCVD risk factors for these patients can be useful (1) as a guide to the potential benefit of statin therapy and (2) for monitoring or adjusting lipid-lowering drug therapy before, and 4 to 12 weeks after, starting inflammatory disease-modifying therapy or antiretroviral therapy.

In adults with rheumatoid arthritis who undergo ASCVD risk assessment with a lipid profile, it can be useful to recheck lipid values and other major ASCVD risk factors 2 to 4 months after the inflammatory disease has been controlled.¹

Primary hypercholesterolemia

The diagnosis and management of heterozygous or homozygous familial hypercholesterolemia (HeFH or HoFH) is beyond the scope of the 2018 ACC/AHA cholesterol guidelines; instead, the 2015 AHA Scientific Statement, “The Agenda for Familial Hypercholesterolemia,” provides a contemporary review of these topics.²³ However, the 2018 cholesterol guideline does acknowledge that an LDL-C level ≥ 190 mg/dL often corresponds to primary (ie, genetic) hypercholesterolemia.

In patients 20 to 75 years of age who have a primary elevation of LDL-C level ≥ 190 mg/dL, the guideline recommends initiation of high-intensity statin therapy without calculating ASCVD risk using the PCE. If a > 50% LDL-C reduction is not achieved, or if the LDL-C level on maximally tolerated statin therapy remains ≥ 100 mg/dL, adding ezetimibe is considered reasonable. If there is < 50% reduction in the LDL-C level while taking maximally tolerated statin and ezetimibe therapy, adding a bile-acid sequestrant can be considered, as long as the TG level is not > 300 mg/dL (ie, bile-acid sequestrants can elevate the TG level significantly).

Continue to: In patients 30 to 75 years of age...

In patients 30 to 75 years of age who have a diagnosis of HeFH and an LDL-C level ≥ 100 mg/dL while taking maximally tolerated statin and ezetimibe therapy, the addition of a PCSK9 inhibitor can be considered. Regardless of whether there is a diagnosis of HeFH, addition of a PCSK9 inhibitor can be considered in patients 40 to 75 years of age who have a baseline LDL-C level ≥ 220 mg/dL and who achieve an on-treatment LDL-C level ≥ 130 mg/dL while receiving maximally tolerated statin therapy and ezetimibe.¹

Diabetes mellitus

In patients with DM who are 40 to 75 years of age, moderate-intensity statin therapy is recommended without calculating the 10-year ASCVD risk. When the LDL-C level is 70 to 189 mg/dL, however, it is reasonable to use the PCE to assess 10-year ASCVD risk to facilitate risk stratification.

In patients 20 to 75 years of age who have a primary elevation of LDL-C level ≥ 190 mg/dL, the guideline recommends initiation of high-intensity statin therapy without calculating ASCVD risk.

In patients with DM who are at higher risk, especially those who have multiple risk factors or are 50 to 75 years of age, it is reasonable to use a high-intensity statin to reduce the LDL-C level by ≥ 50 %. In adults > 75 years of age with DM who are already on statin therapy, it is reasonable to continue statin therapy; for those that age who are not on statin therapy, it might be reasonable to initiate statin therapy after a physician–patient discussion of potential benefits and risks.

In adults with DM and PCE-calculated risk ≥ 20%, it might be reasonable to add ezetimibe to maximally tolerated statin therapy to reduce the LDL-C level by ≥ 50%. In adults 20 to 39 years of age with DM of long duration (≥ 10 years of type 2 DM, ≥ 20 years of type 1 DM), albuminuria (≥ 30 μg of albumin/mg creatinine), estimated glomerular filtration rate < 60 mL/min/1.73 m², retinopathy, neuropathy, or ankle-brachial index < 0.9, it might be reasonable to initiate statin therapy.¹

Secondary prevention

Presence of clinical ASCVD. In patients with clinical ASCVD who are ≤ 75 years of age, high-intensity statin therapy should be initiated or continued, with the aim of achieving ≥ 50% reduction in the LDL-C level. When high-intensity statin therapy is contraindicated or if a patient experiences statin-associated adverse effects, moderate-intensity statin therapy should be initiated or continued with the aim of achieving a 30% to 49% reduction in the LDL-C level.

Continue to: In patients...

In patients > 75 years of age with clinical ASCVD, it is reasonable to initiate or continue moderate- or high-intensity statin therapy after evaluation of the potential for ASCVD risk reduction, adverse effects, and drug–drug interactions, as well as patient frailty and patient preference.¹

Very high risk. In patients at very high risk (this includes a history of multiple major ASCVD events or 1 major ASCVD event plus multiple high-risk conditions), maximally tolerated LDL-C-lowering therapy should include maximally tolerated statin therapy and ezetimibe before considering a PCSK9 inhibitor. An LDL-C level ≥ 70 mg/dL or a non-HDL-C level ≥ 100 mg/dL is considered a reasonable threshold for adding a PCSK9 inhibitor to background lipid-lowering therapy¹ (TABLE 3¹).

Heart failure. In patients with heart failure who have (1) a reduced ejection fraction attributable to ischemic heart disease, (2) a reasonable life expectancy (3-5 years), and (3) are not already on a statin because of ASCVD, consider initiating moderate-intensity statin therapy to reduce the risk for an ASCVD event.¹

Reduction of elevated triglycerides

The guideline defines moderate hypertriglyceridemia as a nonfasting or fasting TG level of 175 to 499 mg/dL. Such a finding is considered a risk-enhancing factor and is 1 of 5 components of the metabolic syndrome. Three independent measurements are advised to diagnose primary moderate hypertriglyceridemia. Severe hypertriglyceridemia is diagnosed when the fasting TG level is ≥ 500 mg/dL.¹

In moderate hypertriglyceridemia, most TGs are carried in very-low-density lipoprotein particles; in severe hypertriglyceridemia, on the other hand, chylomicrons predominate, raising the risk for pancreatitis. In adults with severe hypertriglyceridemia, therefore—especially when the fasting TG level is ≥ 1000 mg/dL—it is reasonable to identify and address other causes of hypertriglyceridemia. If TGs are persistently elevated or increasing, levels should be reduced to prevent acute pancreatitis with a very low-fat diet and by avoiding refined carbohydrates and alcohol; consuming omega-3 fatty acids; and, if necessary, taking a fibrate.¹

Continue to: In adults...

In adults ≥ 20 years of age with moderate hypertriglyceridemia, lifestyle factors (eg, obesity, metabolic syndrome), secondary factors (eg, DM, chronic liver or kidney disease, nephrotic syndrome, hypothyroidism), and medications that increase the TG level need to be addressed first. In adults 40 to 75 years of age with moderate or severe hypertriglyceridemia and a PCE-calculated ASCVD risk ≥ 7.5%, it is reasonable to reevaluate risk after lifestyle and secondary factors are addressed and to consider a persistently elevated TG level as a factor favoring initiation or intensification of statin therapy. In adults 40 to 75 years of age with severe hypertriglyceridemia and ASCVD risk ≥ 7.5%, it is reasonable to address reversible causes of a high TG level and to initiate statin therapy.¹

Other considerations in cholesterol management

Tools to assess adherence

The response to lifestyle and statin therapy should be evaluated by the percentage reduction in the LDL-C level compared with baseline, not by assessment of the absolute LDL-C level. When seeing a patient whose treatment is ongoing, a baseline level can be estimated using a desktop LDL-calculator app.

When pregnancy is planned, statin therapy should be discontinued 1-2 months before pregnancy is attempted.

Adherence and percentage response to LDL-C–lowering medications and lifestyle changes should be evaluated with repeat lipid measurement 4 to 12 weeks after either a statin is initiated or the dosage is adjusted, and repeated every 3 to 12 months as needed. In patients with established ASCVD who are at very high risk, triggers for adding nonstatin therapy are defined by a threshold LDL-C level ≥ 70 mg/dL on maximal statin therapy.¹

Interventions focused on improving adherence to prescribed therapy are recommended for management of adults with an elevated cholesterol level. These interventions include telephone reminders, calendar reminders, integrated multidisciplinary educational activities, and pharmacist-led interventions, such as simplification of the medication regimen to once-daily dosing.¹

Statin safety and associated adverse effects

A physician–patient risk discussion is recommended before initiating statin therapy to review net clinical benefit, during which the 2 parties weigh the potential for ASCVD risk reduction against the potential for statin-associated adverse effects, statin–drug interactions, and safety, with the physician emphasizing that adverse effects can be addressed successfully.

Continue to: Statins are one of...

Statins are one of the safest classes of medication, with an excellent risk-benefit ratio. However, there are myriad confusing media reports regarding potential adverse effects and safety of the statin class—reports that often lead patients to discontinue or refuse statins.

Statin-associated adverse effects include the common statin-associated muscle symptoms (SAMS), new-onset DM, cognitive effects, and hepatic injury. The frequency of new-onset DM depends on the population exposed to statins, with a higher incidence of new-onset DM found in patients who are already predisposed, such as those with obesity, prediabetes, and metabolic syndrome. Cognitive effects are rare and difficult to interpret; they were not reported in the large statin mega-trials but have been described in case reports. Significant transaminase elevations > 3 times the upper limit of normal are infrequent; hepatic failure with statins is extremely rare and found at the same incidence in the general population.¹

SAMS include (in order of decreasing prevalence)²⁴:

• myalgias with a normal creatine kinase (CK) level
• conditions such as myositis or myopathy (elevated CK level)
• rhabdomyolysis (CK level > 10 times the upper limit of normal, plus renal injury)
• extremely rare statin-associated autoimmune myopathy, with detectable 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase antibodies.

In patients with SAMS, thorough assessment of symptoms is recommended, in addition to evaluation for nonstatin causes and predisposing factors. Identification of potential SAMS-predisposing factors is recommended before initiation of treatment, including demographics (eg, East-Asian ancestry), comorbid conditions (eg, hypothyroidism and vitamin D deficiency), and use of medications adversely affecting statin metabolism (eg, cyclosporine).

In patients with statin-associated adverse effects that are not severe, it is recommended to reassess and rechallenge to achieve a maximal lowering of the LDL-C level by a modified dosing regimen or an alternate statin or by combining a statin with nonstatin therapy. In patients with increased risk for DM or new-onset DM, it is recommended to continue statin therapy.

Continue to: Routine CK and liver function testing...

Routine CK and liver function testing is not useful in patients treated with statins; however, it is recommended that CK be measured in patients with severe SAMS or objective muscle weakness, or both, and to measure liver function if symptoms suggest hepatotoxicity. In patients at increased risk for ASCVD who have chronic, stable liver disease (including non-alcoholic fatty liver disease), it is reasonable, when appropriately indicated, to use statins after obtaining baseline measurements and determining a schedule of monitoring and safety checks.

Implementing the 2018 guideline in practice might remain a challenge to clinicians who are inexperienced in ordering lipid markers such as Lp(a) and interpreting the CAC score.

In patients at increased risk for ASCVD who have severe or recurrent SAMS after appropriate statin rechallenge, it is reasonable to use nonstatin therapy that is likely to provide net clinical benefit. The guideline does not recommend routine use of coenzyme Q10 supplementation for the treatment or prevention of SAMS.¹

Guideline criticism

Guideline development is challenging on multiple levels, including balancing perspectives from multiple stakeholders. Nevertheless, the 2018 AHA/ACC cholesterol guideline builds nicely on progress made since its 2013 predecessor was released.⁴ This document was developed with the participation of representatives from 10 professional societies in addition to the ACC and AHA—notably, the National Lipid Association and American Society for Preventive Cardiology.¹

To refine risk estimation and facilitate shared decision-making, the new guideline introduced so-called risk-enhancing factors and use of the CAC.¹ However, some potential risk-enhancing factors were left out: erectile dysfunction, for example, often a marker of increased cardiovascular risk in men < 50 years of age.²⁵ In addition, although pretreatment ApoB was introduced as a risk-enhancing factor,¹ no recommendation is given to measure ApoB after initiation of therapy for evaluation of residual cardiovascular risk, as endorsed in other guidelines.^26,27

Moreover, the guideline does not include the “extreme risk” category in the guideline developed by the American Association of Clinical Endocrinologists (AACE).²⁸ Although the 2018 AHA/ACC guideline introduces < 70 mg/dL and < 100 mg/dL LDL-C thresholds,¹ the < 55 mg/dL LDL-C threshold used for patients in the AACE/American College of Endocrinology extreme-risk category is not mentioned.²⁶ This omission might leave patients who are at extreme ASCVD risk without optimal lipid-lowering therapy. Similarly, the guideline does not elaborate on the diagnosis and treatment of HoFH and HeFH.¹ The age cutoff of 30 years for the recommendation to consider PCSK9 inhibitors in patients with HeFH appears arbitrary and excludes younger FH patients who have an extreme LDL-C elevation from potentially important therapy.²³

Continue to: Guidelines are dynamic instruments...

Guidelines are dynamic instruments that require constant updating, given the production of new evidence. In fact, the results of the Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial (REDUCE-IT) were presented at the same meeting at which this guideline was unveiled.²⁹ REDUCE-IT demonstrated an astonishing highly significant 25% reduction in the composite primary major adverse cardiovascular event outcome in patients with an LDL-C level of 44 to 100 mg/dL on statin therapy, who had a TG level of 135 to 499 mg/dL and had been treated for a median of 4.9 years with 4 g of pure eicosapentaenoic acid.

In addition, the guideline’s value statements, which address the need to consider the cost of drugs in determining most appropriate treatment, are no longer accurate because the price of PCSK9 inhibitors has dropped by more than half since the guideline was issued.³⁰

An upward climb to clinical payoff

Even after close study of the 2018 AHA/ACC cholesterol guideline, implementing it in practice might remain a challenge to clinicians who are inexperienced in ordering lipid markers such as Lp(a) and interpreting the CAC score. Moreover, initiating and monitoring nonstatin therapies will be a demanding task—especially with PCSK9 inhibitors, which present access difficulties because they are relatively expensive (even after the recent price cut). That’s why, when there is doubt in the mind of the physician or other provider, we will likely see more referrals to specialists in lipid management and ASCVD risk estimation to optimize preventive therapy.³¹

CORRESPONDENCE
Cezary Wójcik, MD, PhD, FNLA, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239; [email protected]

A new cholesterol guideline¹ builds on the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol guidelines,² which were a major paradigm shift in the evaluation and management of blood cholesterol levels and risk for atherosclerotic cardiovascular disease (ASCVD). The work was presented (and simultaneously published) on November 10, 2018, at the annual AHA Scientific Sessions in Chicago. Full text,¹ an executive summary,³ and accompanying systematic review of evidence⁴ are available online.

The 2018 AHA/ACC cholesterol guideline represents a step forward in ASCVD prevention—especially in primary prevention, where it provides guidance for risk refinement and personalization. In this article, we mine the details of what has changed and what is new in this guideline so that you can prepare to adopt the recommendations in your practice.

IMAGE: © JOE GORMAN

2013 and 2018 guidelines: Similarities, differences

As in earlier iterations, the 2018 guideline emphasizes healthy lifestyle across the life-course as the basis of ASCVD prevention—as elaborated in the 2013 AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk.⁵ In contrast to the 2013 guidelines,² the 2018 guideline is more comprehensive and more personalized, focusing on risk assessment for individual patients, rather than simply providing population-based approaches. Moreover, the guideline isn’t limited to adults: It makes recommendations pertaining to children and adolescents.¹

TABLE 1^1,2 compares the most important differences between the 2013 and 2018 guidelines.

In contrast to the 2013 guidelines, the 2018 guideline is more comprehensive and more personalized, focusing on risk assessment for individual patients, rather than simply providing population-based approaches.

The 2013 ACC/AHA guidelines eliminated low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C)^a goals of therapy and replaced them with the concept of 4 “statin benefit groups”—that is, patient populations for which clear evidence supports the role of statin therapy.⁴ In the 2018 guideline, statin benefit groups have been maintained, although without explicit use of this term.¹

Primary prevention. Although no major changes in statin indications are made for patients with (1) established ASCVD (ie, for secondary prevention), (2) diabetes mellitus (DM) and who are 40 to 75 years of age, or (3) a primary LDL-C elevation ≥ 190 mg/dL, significant changes were made for primary prevention patients ages 40 to 75 years.¹ ASCVD risk calculation using the 2013 pooled cohort equations (PCE) is still recommended⁴; however, risk estimation is refined by the use of specific so-called risk-enhancing factors (TABLE 2¹). In cases in which the risk decision remains uncertain, obtaining the coronary artery calcium (CAC) score (which we’ll describe shortly) using specialized computed tomography (CT) is advised to facilitate the shared physician–patient decision-making process.¹

LDL-C and non-HDL-C thresholds. Although LDL-C and non-HDL-C goals are not overtly brought back from the 2002 National Cholesterol Education Program/Adult Treatment Panel guidelines,⁶ the new guideline does introduce LDL-C and non-HDL-C thresholds—levels at which adding nonstatin therapy can be considered, in contrast to previous goals to which therapy was titrated. Definitions of statin intensity remain the same: Moderate-intensity statin therapy is expected to reduce the LDL-C level by 30% to 50%; high-intensity statin therapy, by ≥ 50%.¹ The intensity of statin therapy has been de-escalated in the intermediate-risk group, where previous guidelines advised high-intensity statin therapy,⁴ and replaced with moderate-intensity statin therapy (similar to 2016 US Preventive Services Task Force [USPSTF] recommendations⁷).

[polldaddy:10312157]

Continue to: Fasting vs nonfasting lipid profiles

Fasting vs nonfasting lipid profiles. In contrast to previous guidelines,^2,8 which used fasting lipid profiles, nonfasting lipid profiles are now recommended for establishing a baseline LDL-C level and for ASCVD risk estimation for most patients—as long as the triglycerides (TG) level is < 400 mg/dL. When the calculated LDL-C level is < 70 mg/dL using the standard Friedewald formula, obtaining a direct LDL-C or a modified LDL-C estimate⁹ is deemed reasonable to improve accuracy. (The modified LDL-C can be estimated using The Johns Hopkins Hospital’s free “LDL Cholesterol Calculator” [www.hopkinsmedicine.org/apps/all-apps/ldl-cholesterol-calculator]).

A fasting lipid profile is still preferred for patients who have a family history of a lipid disorder. The definition of hypertriglyceridemia has been revised from a fasting TG level ≥ 150 mg/dL to a nonfasting or fasting TG level ≥ 175 mg/dL.¹

Nonstatin add-on therapy. The new guideline supports the addition of nonstatin therapies to maximally tolerated statin therapy in patients who have established ASCVD or a primary LDL-C elevation ≥ 190 mg/dL when (1) the LDL-C level has not been reduced by the expected percentage (≥ 50% for high-intensity statin therapy) or (2) explicit LDL-C level thresholds have been met.¹

Although measurement of the coronary artery calcium score by CT is generally not covered by insurance, its cost ($50-$450) nationwide makes it accessible.

The principal 2 groups of recommended nonstatins for which there is randomized, controlled trial evidence of cardiovascular benefit are (1) the cholesterol-absorbing agent ezetimibe¹⁰ and (2) the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors evolocumab¹¹ and alirocumab.¹²

AAFP’s guarded positions on the 2013 and 2018 guidelines

The American Academy of Family Physicians (AAFP) welcomed the patient-centered and outcome-oriented aspects of the 2013 ACC/AHA guidelines, endorsing them with 3 qualifications.¹³

1. Many of the recommendations were based on expert opinion, not rigorous research results—in particular, not on the findings of randomized controlled trials (although key points are based on high-quality evidence).
2. There were conflicts of interest disclosed for 15 members of the guidelines panel, including a vice chair.
3. Validation of the PCE risk estimation tool was lacking.

Continue to: AAFP announced...

AAFP announced in March that it does not endorse the 2018 AHA/ACC guideline, asserting that (1) only a small portion of the recommendations, primarily focused on the addition of nonstatin therapy, were addressed by an independent systematic review and (2) many of the guideline recommendations are based on low-quality or insufficient evidence. AAFP nevertheless bestowed an “affirmation of value” designation on the guideline—meaning that it provides some benefit for family physicians’ practice without fulfilling all criteria for full endorsement.¹⁴

Detailed recommendations from the 2018 guideline

Lifestyle modification

When talking about ASCVD risk with patients, it is important to review current lifestyle habits (eg, diet, physical activity, weight or body mass index, and tobacco use). Subsequent to that conversation, a healthy lifestyle should be endorsed and relevant advice provided. In addition, patient-directed materials (eg, ACC’s CardioSmart [www.cardiosmart.org]; AHA’s Life’s Simple 7 [www.heart.org/en/professional/workplace-health/lifes-simple-7]; and the National Lipid Association’s Patient Tear Sheets [www.lipid.org/practicetools/tools/tearsheets] and Clinicians’ Lifestyle Modification Toolbox [www.lipid.org/CLMT]) and referrals (eg, to cardiac rehabilitation, a dietitian, a smoking-cessation program) should be provided.¹

Primary prevention of ASCVD

Risk assessment for primary prevention is now approached as a process, rather than the simple risk calculation used in the 2013 ACC/AHA guidelines.² Assessment involves risk estimation followed by risk personalization, which, in some cases, is followed by risk reclassification using CAC scoring.¹

Patients are classified into 1 of 4 risk groups, based on the PCE¹:

• low (< 5%)
• borderline (5%-7.5%)
• intermediate (7.5%-19.9%)
• high (≥ 20%).

However, the PCE-based risk score is a population-based tool, which might not reflect the actual risk of individual patients. In some populations, PCE underestimates ASCVD risk; in others, it overestimates risk. A central tenet of the new guideline is personalization of risk, taking into account the unique circumstances of each patient. Moreover, the new guideline provides guidance on how to interpret the PCE risk score for several different ethnic and racial groups.¹

Continue to: Medical therapy

Medical therapy. The decision to start lipid-lowering therapy should be made after a physician–patient discussion that considers costs of therapy as well as patient preferences and values in the context of shared decision-making. Discussion should include a review of major risk factors (eg, cigarette smoking, elevated blood pressure, and the LDL-C level), the PCE risk score, the presence of risk-enhancing factors (TABLE 2¹), potential benefits of lifestyle changes and statin therapy, and the potential for adverse drug effects and drug–drug interactions.¹

If the estimated ASCVD risk is 7.5%-19.9%, starting moderate-intensity statin therapy is recommended. Risk-enhancing factors favor initiation of statin therapy, even in patients at borderline risk (5%-7.5%). If risk is uncertain, the CAC score can be used to facilitate shared decision-making.¹ The use of CAC is in agreement with the USPSTF statement that CAC can moderately improve discrimination and reclassification, but has an unclear effect on downstream health care utilization.¹⁵ Importantly, CAC should not be measured routinely in patients already taking a statin because its primary role is to facilitate shared decision-making regarding initiation of statin therapy.¹⁶

If the 10-year ASCVD risk is ≥ 20%, high-intensity statin therapy is advised, without need to obtain the CAC score. If high-intensity statin therapy is advisable but not acceptable to, or tolerated by, the patient, it might be reasonable to add a nonstatin drug (ezetimibe or a bile-acid sequestrant) to moderate-intensity statin therapy.¹

Risk-enhancing factors (TABLE 2¹) apply to intermediate- and borderline-risk patients. Importantly, these factors include membership in specific ethnic groups, conditions specific to females, and male–female distinctions in risk. Risk-enhancing factors also incorporate biomarkers that are often measured by lipid specialists, such as lipoprotein(a) (Lp[a]) and apolipoprotein B (ApoB).¹

Lp(a) is an atherogenic particle, akin to an LDL particle, that consists of a molecule of apolipoprotein (a) (a nonfunctional mimic of a portion of plasminogen) covalently bound to ApoB, like the one found on the LDL particle. Lp(a) is proportionally associated with an increased risk for ASCVD and aortic stenosis at a level > 50 mg/dL.¹⁷ A family history of premature ASCVD is a relative indication for measuring Lp(a).¹

Continue to: When and why to measure CAC

When and why to measure CAC

If the decision to initiate statin therapy is still uncertain after risk estimation and personalization, or when a patient is undecided about committing to lifelong lipid-lowering therapy, the new guideline recommends obtaining a CAC score to inform the shared decision-making process.^1,18 Measurement of CAC is obtained by noncontrast, electrocardiographic-gated CT that can be performed in 10 to 15 minutes, requiring approximately 1 millisievert of radiation (equivalent of the approximate dose absorbed during 2 mammograms). Although measurement of the CAC score is generally not covered by insurance, its cost ($50-$450) nationwide makes it accessible.¹⁹

The guideline endorses reverse cascade screening for detection of familial hypercholesterolemia in family members of children and adolescents who have severe hypercholesterolemia.

CAC measures the presence (or absence) of subclinical atherosclerosis by detecting calcified plaque in coronary arteries. The absolute CAC score is expressed in Agatston units; an age–gender population percentile is also provided. Keep in mind that the presence of any CAC (ie, a score > 0) is abnormal and demonstrates the presence of subclinical coronary artery disease. The prevalence of CAC > 0 increases with age, but a significant percentage of older people have a CAC score = 0. When CAC > 0, additional information is provided by the distribution of plaque burden among the different coronary arteries.²⁰

Among intermediate-risk patients, 50% have CAC = 0 and, therefore, a very low event rate over the ensuing 10 years, which allows statin therapy to be safely deferred unless certain risk factors are present (eg, family history, smoking, DM).^1,18 It is reasonable to repeat CAC testing in 5 to 10 years to assess whether subclinical atherosclerosis has developed. The 2018 guideline emphasizes that, when the CAC score is > 0 but < 100 Agatston units, statin therapy is favored, especially in patients > 55 years of age; when the CAC score is ≥ 100 Agatston units or at the ≥ 75th percentile, statin therapy is indicated regardless of age.¹

Patients who might benefit from knowing their CAC score include those who are:

• reluctant to initiate statin therapy but who want to understand their risk and potential for benefit more precisely
• concerned about the need to reinstitute statin therapy after discontinuing it because of statin-associated adverse effects
• older (men, 55-80 years; women, 60-80 years) who have a low burden of risk factors and who question whether they would benefit from statin therapy
• middle-aged (40-55 years) and who have a PCE-calculated risk of 5% to < 7.5% for ASCVD and factors that increase their risk for ASCVD, even though they are in a borderline-risk group.¹

Primary prevention in special populations

Older patients. In adults ≥ 75 years who have an LDL-C level 70 to 189 mg/dL, initiating a moderate-intensity statin might be reasonable; however, it might also be reasonable to stop treatment in this population when physical or cognitive decline, multiple morbidities, frailty, or reduced life expectancy limits the potential benefit of statin therapy. It might be reasonable to use the CAC score in adults 76 to 80 years of age who have an LDL-C level of 70 to 189 mg/dL to reclassify those whose CAC score = 0, so that they can avoid statin therapy.¹

Continue to: Children and adolescents

Children and adolescents. In alignment with current pediatric guidelines,²¹ but in contrast to USPSTF reccomendations,²² the 2018 ACC/AHA guideline endorses universal lipid screening for pediatric patients (see TABLE W1^1,21,22). It is reasonable to obtain a fasting lipid profile or nonfasting non-HDL-C in all children and adolescents who have neither cardiovascular risk factors nor a family history of early cardiovascular disease to detect moderate-to-severe lipid abnormalities. Screening should be done once at 9 to 11 years of age and again at 17 to 21 years.¹

A screening test as early as 2 years of age to detect familial hypercholesterolemia (FH) is reasonable when a family history of either early CVD or significant hypercholesterolemia is present. The guideline endorses reverse cascade screening for detection of FH in family members of children and adolescents who have severe hypercholesterolemia.¹

Risk-enhancing factors favor initiation of statin therapy, even in patients at borderline risk.

In children and adolescents with a lipid abnormality, especially when associated with the metabolic syndrome, lifestyle counseling is beneficial for lowering the LDL-C level. In children and adolescents ≥ 10 years of age with (1) an LDL-C level persistently ≥ 190 mg/dL or (2) an LDL level ≥ 160 mg/dL plus a clinical presentation consistent with FH, it is reasonable to initiate statin therapy if they do not respond adequately to 3 to 6 months of lifestyle therapy.¹

Ethnicity as a risk-modifying factor. The PCE distinguishes between US adults of European ancestry and African ancestry, but no other ethnic groups are distinguished.⁴ The new guideline advocates for the use of PCE in other populations; however, it states that, for clinical decision-making purposes, it is reasonable, in adults of different races and ethnicities, for the physician to review racial and ethnic features that can influence ASCVD risk to allow adjustment of the choice of statin or intensity of treatment. Specifically, South Asian ancestry is now treated as a risk-enhancing factor, given the high prevalence of premature and extensive ASCVD in this patient population.¹

Concerns specific to women. Considering conditions specific to women as potential risk-enhancing factors is advised when discussing lifestyle intervention and the potential for benefit from statin therapy—in particular, (1) in the setting of premature menopause (< 40 years) and (2) when there is a history of a pregnancy-associated disorder (eg, hypertension, preeclampsia, gestational DM, a small-for-gestational-age infant, and preterm delivery). If the decision is made to initiate statin therapy in women of childbearing age who are sexually active, there is a guideline mandate to counsel patients on using reliable contraception. When pregnancy is planned, statin therapy should be discontinued 1 to 2 months before pregnancy is attempted; when pregnancy occurs while a patient is taking a statin, therapy should be stopped as soon as the pregnancy is discovered.¹

Continue to: Adults with chronic kidney disease

Adults with chronic kidney disease. Chronic kidney disease that is not treated with dialysis or kidney transplantation is considered a risk-enhancing factor; initiation of a moderate-intensity statin or a moderate-intensity statin plus ezetimibe can be useful in patients with chronic kidney disease who are 40 to 75 years of age and have an LDL-C level of 70 to 189 mg/dL and a PCE-calculated risk ≥ 7.5%. In adults with advanced kidney disease that requires dialysis who are already taking a statin, it may be reasonable to continue the statin; however, initiation of a statin in adults with advanced kidney disease who require dialysis is not recommended because of an apparent lack of benefit.¹

Adults with a chronic inflammatory disorder or human immunodeficiency virus infection. Any of these conditions are treated as risk-enhancing factors; in a risk discussion with affected patients, therefore, moderate-intensity statin therapy or high-intensity statin therapy is favored for those 40 to 75 years of age who have an LDL-C level of 70 to 189 mg/dL and PCE-calculated risk ≥ 7.5%. A fasting lipid profile and assessment of ASCVD risk factors for these patients can be useful (1) as a guide to the potential benefit of statin therapy and (2) for monitoring or adjusting lipid-lowering drug therapy before, and 4 to 12 weeks after, starting inflammatory disease-modifying therapy or antiretroviral therapy.

In adults with rheumatoid arthritis who undergo ASCVD risk assessment with a lipid profile, it can be useful to recheck lipid values and other major ASCVD risk factors 2 to 4 months after the inflammatory disease has been controlled.¹

Primary hypercholesterolemia

The diagnosis and management of heterozygous or homozygous familial hypercholesterolemia (HeFH or HoFH) is beyond the scope of the 2018 ACC/AHA cholesterol guidelines; instead, the 2015 AHA Scientific Statement, “The Agenda for Familial Hypercholesterolemia,” provides a contemporary review of these topics.²³ However, the 2018 cholesterol guideline does acknowledge that an LDL-C level ≥ 190 mg/dL often corresponds to primary (ie, genetic) hypercholesterolemia.

In patients 20 to 75 years of age who have a primary elevation of LDL-C level ≥ 190 mg/dL, the guideline recommends initiation of high-intensity statin therapy without calculating ASCVD risk using the PCE. If a > 50% LDL-C reduction is not achieved, or if the LDL-C level on maximally tolerated statin therapy remains ≥ 100 mg/dL, adding ezetimibe is considered reasonable. If there is < 50% reduction in the LDL-C level while taking maximally tolerated statin and ezetimibe therapy, adding a bile-acid sequestrant can be considered, as long as the TG level is not > 300 mg/dL (ie, bile-acid sequestrants can elevate the TG level significantly).

Continue to: In patients 30 to 75 years of age...

In patients 30 to 75 years of age who have a diagnosis of HeFH and an LDL-C level ≥ 100 mg/dL while taking maximally tolerated statin and ezetimibe therapy, the addition of a PCSK9 inhibitor can be considered. Regardless of whether there is a diagnosis of HeFH, addition of a PCSK9 inhibitor can be considered in patients 40 to 75 years of age who have a baseline LDL-C level ≥ 220 mg/dL and who achieve an on-treatment LDL-C level ≥ 130 mg/dL while receiving maximally tolerated statin therapy and ezetimibe.¹

Diabetes mellitus

In patients with DM who are 40 to 75 years of age, moderate-intensity statin therapy is recommended without calculating the 10-year ASCVD risk. When the LDL-C level is 70 to 189 mg/dL, however, it is reasonable to use the PCE to assess 10-year ASCVD risk to facilitate risk stratification.

In patients 20 to 75 years of age who have a primary elevation of LDL-C level ≥ 190 mg/dL, the guideline recommends initiation of high-intensity statin therapy without calculating ASCVD risk.

In patients with DM who are at higher risk, especially those who have multiple risk factors or are 50 to 75 years of age, it is reasonable to use a high-intensity statin to reduce the LDL-C level by ≥ 50 %. In adults > 75 years of age with DM who are already on statin therapy, it is reasonable to continue statin therapy; for those that age who are not on statin therapy, it might be reasonable to initiate statin therapy after a physician–patient discussion of potential benefits and risks.

In adults with DM and PCE-calculated risk ≥ 20%, it might be reasonable to add ezetimibe to maximally tolerated statin therapy to reduce the LDL-C level by ≥ 50%. In adults 20 to 39 years of age with DM of long duration (≥ 10 years of type 2 DM, ≥ 20 years of type 1 DM), albuminuria (≥ 30 μg of albumin/mg creatinine), estimated glomerular filtration rate < 60 mL/min/1.73 m², retinopathy, neuropathy, or ankle-brachial index < 0.9, it might be reasonable to initiate statin therapy.¹

Secondary prevention

Presence of clinical ASCVD. In patients with clinical ASCVD who are ≤ 75 years of age, high-intensity statin therapy should be initiated or continued, with the aim of achieving ≥ 50% reduction in the LDL-C level. When high-intensity statin therapy is contraindicated or if a patient experiences statin-associated adverse effects, moderate-intensity statin therapy should be initiated or continued with the aim of achieving a 30% to 49% reduction in the LDL-C level.

Continue to: In patients...

In patients > 75 years of age with clinical ASCVD, it is reasonable to initiate or continue moderate- or high-intensity statin therapy after evaluation of the potential for ASCVD risk reduction, adverse effects, and drug–drug interactions, as well as patient frailty and patient preference.¹

Very high risk. In patients at very high risk (this includes a history of multiple major ASCVD events or 1 major ASCVD event plus multiple high-risk conditions), maximally tolerated LDL-C-lowering therapy should include maximally tolerated statin therapy and ezetimibe before considering a PCSK9 inhibitor. An LDL-C level ≥ 70 mg/dL or a non-HDL-C level ≥ 100 mg/dL is considered a reasonable threshold for adding a PCSK9 inhibitor to background lipid-lowering therapy¹ (TABLE 3¹).

Heart failure. In patients with heart failure who have (1) a reduced ejection fraction attributable to ischemic heart disease, (2) a reasonable life expectancy (3-5 years), and (3) are not already on a statin because of ASCVD, consider initiating moderate-intensity statin therapy to reduce the risk for an ASCVD event.¹

Reduction of elevated triglycerides

The guideline defines moderate hypertriglyceridemia as a nonfasting or fasting TG level of 175 to 499 mg/dL. Such a finding is considered a risk-enhancing factor and is 1 of 5 components of the metabolic syndrome. Three independent measurements are advised to diagnose primary moderate hypertriglyceridemia. Severe hypertriglyceridemia is diagnosed when the fasting TG level is ≥ 500 mg/dL.¹

In moderate hypertriglyceridemia, most TGs are carried in very-low-density lipoprotein particles; in severe hypertriglyceridemia, on the other hand, chylomicrons predominate, raising the risk for pancreatitis. In adults with severe hypertriglyceridemia, therefore—especially when the fasting TG level is ≥ 1000 mg/dL—it is reasonable to identify and address other causes of hypertriglyceridemia. If TGs are persistently elevated or increasing, levels should be reduced to prevent acute pancreatitis with a very low-fat diet and by avoiding refined carbohydrates and alcohol; consuming omega-3 fatty acids; and, if necessary, taking a fibrate.¹

Continue to: In adults...

In adults ≥ 20 years of age with moderate hypertriglyceridemia, lifestyle factors (eg, obesity, metabolic syndrome), secondary factors (eg, DM, chronic liver or kidney disease, nephrotic syndrome, hypothyroidism), and medications that increase the TG level need to be addressed first. In adults 40 to 75 years of age with moderate or severe hypertriglyceridemia and a PCE-calculated ASCVD risk ≥ 7.5%, it is reasonable to reevaluate risk after lifestyle and secondary factors are addressed and to consider a persistently elevated TG level as a factor favoring initiation or intensification of statin therapy. In adults 40 to 75 years of age with severe hypertriglyceridemia and ASCVD risk ≥ 7.5%, it is reasonable to address reversible causes of a high TG level and to initiate statin therapy.¹

Other considerations in cholesterol management

Tools to assess adherence

The response to lifestyle and statin therapy should be evaluated by the percentage reduction in the LDL-C level compared with baseline, not by assessment of the absolute LDL-C level. When seeing a patient whose treatment is ongoing, a baseline level can be estimated using a desktop LDL-calculator app.

When pregnancy is planned, statin therapy should be discontinued 1-2 months before pregnancy is attempted.

Adherence and percentage response to LDL-C–lowering medications and lifestyle changes should be evaluated with repeat lipid measurement 4 to 12 weeks after either a statin is initiated or the dosage is adjusted, and repeated every 3 to 12 months as needed. In patients with established ASCVD who are at very high risk, triggers for adding nonstatin therapy are defined by a threshold LDL-C level ≥ 70 mg/dL on maximal statin therapy.¹

Interventions focused on improving adherence to prescribed therapy are recommended for management of adults with an elevated cholesterol level. These interventions include telephone reminders, calendar reminders, integrated multidisciplinary educational activities, and pharmacist-led interventions, such as simplification of the medication regimen to once-daily dosing.¹

Statin safety and associated adverse effects

A physician–patient risk discussion is recommended before initiating statin therapy to review net clinical benefit, during which the 2 parties weigh the potential for ASCVD risk reduction against the potential for statin-associated adverse effects, statin–drug interactions, and safety, with the physician emphasizing that adverse effects can be addressed successfully.

Continue to: Statins are one of...

Statins are one of the safest classes of medication, with an excellent risk-benefit ratio. However, there are myriad confusing media reports regarding potential adverse effects and safety of the statin class—reports that often lead patients to discontinue or refuse statins.

Statin-associated adverse effects include the common statin-associated muscle symptoms (SAMS), new-onset DM, cognitive effects, and hepatic injury. The frequency of new-onset DM depends on the population exposed to statins, with a higher incidence of new-onset DM found in patients who are already predisposed, such as those with obesity, prediabetes, and metabolic syndrome. Cognitive effects are rare and difficult to interpret; they were not reported in the large statin mega-trials but have been described in case reports. Significant transaminase elevations > 3 times the upper limit of normal are infrequent; hepatic failure with statins is extremely rare and found at the same incidence in the general population.¹

SAMS include (in order of decreasing prevalence)²⁴:

• myalgias with a normal creatine kinase (CK) level
• conditions such as myositis or myopathy (elevated CK level)
• rhabdomyolysis (CK level > 10 times the upper limit of normal, plus renal injury)
• extremely rare statin-associated autoimmune myopathy, with detectable 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase antibodies.

In patients with SAMS, thorough assessment of symptoms is recommended, in addition to evaluation for nonstatin causes and predisposing factors. Identification of potential SAMS-predisposing factors is recommended before initiation of treatment, including demographics (eg, East-Asian ancestry), comorbid conditions (eg, hypothyroidism and vitamin D deficiency), and use of medications adversely affecting statin metabolism (eg, cyclosporine).

In patients with statin-associated adverse effects that are not severe, it is recommended to reassess and rechallenge to achieve a maximal lowering of the LDL-C level by a modified dosing regimen or an alternate statin or by combining a statin with nonstatin therapy. In patients with increased risk for DM or new-onset DM, it is recommended to continue statin therapy.

Continue to: Routine CK and liver function testing...

Routine CK and liver function testing is not useful in patients treated with statins; however, it is recommended that CK be measured in patients with severe SAMS or objective muscle weakness, or both, and to measure liver function if symptoms suggest hepatotoxicity. In patients at increased risk for ASCVD who have chronic, stable liver disease (including non-alcoholic fatty liver disease), it is reasonable, when appropriately indicated, to use statins after obtaining baseline measurements and determining a schedule of monitoring and safety checks.

Implementing the 2018 guideline in practice might remain a challenge to clinicians who are inexperienced in ordering lipid markers such as Lp(a) and interpreting the CAC score.

In patients at increased risk for ASCVD who have severe or recurrent SAMS after appropriate statin rechallenge, it is reasonable to use nonstatin therapy that is likely to provide net clinical benefit. The guideline does not recommend routine use of coenzyme Q10 supplementation for the treatment or prevention of SAMS.¹

Guideline criticism

Guideline development is challenging on multiple levels, including balancing perspectives from multiple stakeholders. Nevertheless, the 2018 AHA/ACC cholesterol guideline builds nicely on progress made since its 2013 predecessor was released.⁴ This document was developed with the participation of representatives from 10 professional societies in addition to the ACC and AHA—notably, the National Lipid Association and American Society for Preventive Cardiology.¹

To refine risk estimation and facilitate shared decision-making, the new guideline introduced so-called risk-enhancing factors and use of the CAC.¹ However, some potential risk-enhancing factors were left out: erectile dysfunction, for example, often a marker of increased cardiovascular risk in men < 50 years of age.²⁵ In addition, although pretreatment ApoB was introduced as a risk-enhancing factor,¹ no recommendation is given to measure ApoB after initiation of therapy for evaluation of residual cardiovascular risk, as endorsed in other guidelines.^26,27

Moreover, the guideline does not include the “extreme risk” category in the guideline developed by the American Association of Clinical Endocrinologists (AACE).²⁸ Although the 2018 AHA/ACC guideline introduces < 70 mg/dL and < 100 mg/dL LDL-C thresholds,¹ the < 55 mg/dL LDL-C threshold used for patients in the AACE/American College of Endocrinology extreme-risk category is not mentioned.²⁶ This omission might leave patients who are at extreme ASCVD risk without optimal lipid-lowering therapy. Similarly, the guideline does not elaborate on the diagnosis and treatment of HoFH and HeFH.¹ The age cutoff of 30 years for the recommendation to consider PCSK9 inhibitors in patients with HeFH appears arbitrary and excludes younger FH patients who have an extreme LDL-C elevation from potentially important therapy.²³

Continue to: Guidelines are dynamic instruments...

Guidelines are dynamic instruments that require constant updating, given the production of new evidence. In fact, the results of the Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial (REDUCE-IT) were presented at the same meeting at which this guideline was unveiled.²⁹ REDUCE-IT demonstrated an astonishing highly significant 25% reduction in the composite primary major adverse cardiovascular event outcome in patients with an LDL-C level of 44 to 100 mg/dL on statin therapy, who had a TG level of 135 to 499 mg/dL and had been treated for a median of 4.9 years with 4 g of pure eicosapentaenoic acid.

In addition, the guideline’s value statements, which address the need to consider the cost of drugs in determining most appropriate treatment, are no longer accurate because the price of PCSK9 inhibitors has dropped by more than half since the guideline was issued.³⁰

An upward climb to clinical payoff

Even after close study of the 2018 AHA/ACC cholesterol guideline, implementing it in practice might remain a challenge to clinicians who are inexperienced in ordering lipid markers such as Lp(a) and interpreting the CAC score. Moreover, initiating and monitoring nonstatin therapies will be a demanding task—especially with PCSK9 inhibitors, which present access difficulties because they are relatively expensive (even after the recent price cut). That’s why, when there is doubt in the mind of the physician or other provider, we will likely see more referrals to specialists in lipid management and ASCVD risk estimation to optimize preventive therapy.³¹

CORRESPONDENCE
Cezary Wójcik, MD, PhD, FNLA, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239; [email protected]

Female patients with acne may benefit from continuing treatment with spironolactone longer than with oral antibiotics, according to a retrospective study of women with acne published in the Journal of the American Academy of Dermatology.

VladimirFLoyd/Thinkstock

Among those treated for at least a year, patients continued spironolactone for about 90 days longer on average, than those on antibiotic therapy, reported John S. Barbieri, MD, of the department of dermatology at the University of Pennsylvania, Philadelphia, and associates. “The extended drug usage survival of spironolactone suggests that, in routine clinical practice, spironolactone may have good long-term effectiveness and tolerability,” they wrote. “Since female patients often have persistent acne into adulthood and given concerns regarding antibiotic overuse among acne patients, it is possible that using spironolactone as a first-line agent before oral antibiotics could improve outcomes for female patients with acne,” they added.

In the study, they pointed out that spironolactone is emerging as a possible alternative to oral antibiotic therapy, but “little is known about long-term outcomes with spironolactone for those who have an initial positive response and how it compares to other alternatives.”

To examine the duration of acne treatment with spironolactone versus oral antibiotics, the researchers analyzed data during 2010-2016 in the Optum Clinformatics Data Mart. They included data on female patients aged 12-40 years, with at least two diagnosis codes for acne, who received spironolactone or oral antibiotics for at least 12 months. They used multivariate Cox proportional hazard models to assess differences in duration of therapy for spironolactone, compared with oral antibiotics.

The mean duration of a treatment course was significantly longer among the 4,321 patients treated with spironolactone than among the 7,517 patients treated with oral tetracycline-class antibiotics (697.8 days vs. 604.4 days; P less than .001). Compared with treatment with oral tetracyclines, the hazard ratio for discontinuing spironolactone treatment was 0.74, after researchers controlled for the age at diagnosis and treatment, history of polycystic ovarian syndrome, and history of combined oral contraceptive or topical retinoid treatment.

Patients who receive spironolactone and patients who receive oral antibiotics may represent different populations, the authors noted. In addition, guidelines advise limiting antibiotic treatment to 3-6 months, and antibiotic discontinuations may have been related to these recommendations. “It is not possible to determine whether medication discontinuation occurred due to lack of efficacy, cost, side effects, resolution of acne, or other factors,” they said, adding that prospective studies are needed “to identify the optimal treatment approaches for female patients with moderate to severe acne.”

The study was funded in part by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Barbieri is supported by NIAMS and receives partial salary support through a Pfizer Fellowship in Dermatology Patient Oriented Research grant to the Trustees of the University of Pennsylvania.

[email protected]

SOURCE: Barbieri JS et al. J Am Acad Dermatol. 2019 Mar 21. doi: 10.1016/j.jaad.2019.03.036.

Female patients with acne may benefit from continuing treatment with spironolactone longer than with oral antibiotics, according to a retrospective study of women with acne published in the Journal of the American Academy of Dermatology.

VladimirFLoyd/Thinkstock

Among those treated for at least a year, patients continued spironolactone for about 90 days longer on average, than those on antibiotic therapy, reported John S. Barbieri, MD, of the department of dermatology at the University of Pennsylvania, Philadelphia, and associates. “The extended drug usage survival of spironolactone suggests that, in routine clinical practice, spironolactone may have good long-term effectiveness and tolerability,” they wrote. “Since female patients often have persistent acne into adulthood and given concerns regarding antibiotic overuse among acne patients, it is possible that using spironolactone as a first-line agent before oral antibiotics could improve outcomes for female patients with acne,” they added.

In the study, they pointed out that spironolactone is emerging as a possible alternative to oral antibiotic therapy, but “little is known about long-term outcomes with spironolactone for those who have an initial positive response and how it compares to other alternatives.”

To examine the duration of acne treatment with spironolactone versus oral antibiotics, the researchers analyzed data during 2010-2016 in the Optum Clinformatics Data Mart. They included data on female patients aged 12-40 years, with at least two diagnosis codes for acne, who received spironolactone or oral antibiotics for at least 12 months. They used multivariate Cox proportional hazard models to assess differences in duration of therapy for spironolactone, compared with oral antibiotics.

The mean duration of a treatment course was significantly longer among the 4,321 patients treated with spironolactone than among the 7,517 patients treated with oral tetracycline-class antibiotics (697.8 days vs. 604.4 days; P less than .001). Compared with treatment with oral tetracyclines, the hazard ratio for discontinuing spironolactone treatment was 0.74, after researchers controlled for the age at diagnosis and treatment, history of polycystic ovarian syndrome, and history of combined oral contraceptive or topical retinoid treatment.

Patients who receive spironolactone and patients who receive oral antibiotics may represent different populations, the authors noted. In addition, guidelines advise limiting antibiotic treatment to 3-6 months, and antibiotic discontinuations may have been related to these recommendations. “It is not possible to determine whether medication discontinuation occurred due to lack of efficacy, cost, side effects, resolution of acne, or other factors,” they said, adding that prospective studies are needed “to identify the optimal treatment approaches for female patients with moderate to severe acne.”

The study was funded in part by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Barbieri is supported by NIAMS and receives partial salary support through a Pfizer Fellowship in Dermatology Patient Oriented Research grant to the Trustees of the University of Pennsylvania.

[email protected]

SOURCE: Barbieri JS et al. J Am Acad Dermatol. 2019 Mar 21. doi: 10.1016/j.jaad.2019.03.036.

Female patients with acne may benefit from continuing treatment with spironolactone longer than with oral antibiotics, according to a retrospective study of women with acne published in the Journal of the American Academy of Dermatology.

VladimirFLoyd/Thinkstock

Among those treated for at least a year, patients continued spironolactone for about 90 days longer on average, than those on antibiotic therapy, reported John S. Barbieri, MD, of the department of dermatology at the University of Pennsylvania, Philadelphia, and associates. “The extended drug usage survival of spironolactone suggests that, in routine clinical practice, spironolactone may have good long-term effectiveness and tolerability,” they wrote. “Since female patients often have persistent acne into adulthood and given concerns regarding antibiotic overuse among acne patients, it is possible that using spironolactone as a first-line agent before oral antibiotics could improve outcomes for female patients with acne,” they added.

In the study, they pointed out that spironolactone is emerging as a possible alternative to oral antibiotic therapy, but “little is known about long-term outcomes with spironolactone for those who have an initial positive response and how it compares to other alternatives.”

To examine the duration of acne treatment with spironolactone versus oral antibiotics, the researchers analyzed data during 2010-2016 in the Optum Clinformatics Data Mart. They included data on female patients aged 12-40 years, with at least two diagnosis codes for acne, who received spironolactone or oral antibiotics for at least 12 months. They used multivariate Cox proportional hazard models to assess differences in duration of therapy for spironolactone, compared with oral antibiotics.

The mean duration of a treatment course was significantly longer among the 4,321 patients treated with spironolactone than among the 7,517 patients treated with oral tetracycline-class antibiotics (697.8 days vs. 604.4 days; P less than .001). Compared with treatment with oral tetracyclines, the hazard ratio for discontinuing spironolactone treatment was 0.74, after researchers controlled for the age at diagnosis and treatment, history of polycystic ovarian syndrome, and history of combined oral contraceptive or topical retinoid treatment.

Patients who receive spironolactone and patients who receive oral antibiotics may represent different populations, the authors noted. In addition, guidelines advise limiting antibiotic treatment to 3-6 months, and antibiotic discontinuations may have been related to these recommendations. “It is not possible to determine whether medication discontinuation occurred due to lack of efficacy, cost, side effects, resolution of acne, or other factors,” they said, adding that prospective studies are needed “to identify the optimal treatment approaches for female patients with moderate to severe acne.”

The study was funded in part by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Barbieri is supported by NIAMS and receives partial salary support through a Pfizer Fellowship in Dermatology Patient Oriented Research grant to the Trustees of the University of Pennsylvania.

[email protected]

SOURCE: Barbieri JS et al. J Am Acad Dermatol. 2019 Mar 21. doi: 10.1016/j.jaad.2019.03.036.

The Food and Drug Administration has approved Qternmet XR (dapagliflozin/saxagliptin/metformin) as an oral adjunct therapy to diet and exercise for the improvement of glycemic control in patients with type 2 diabetes, according to AstraZeneca.

Wikimedia Commons/FitzColinGerald/Creative Commons License

FDA approval is based on results from a pair of phase 3 trials that tested different combinations of dapagliflozin and saxagliptin in patients with inadequately controlled type 2 diabetes who were also receiving metformin over a 24-week period. In both trials, treatment with dapagliflozin/saxagliptin/metformin decreased hemoglobin A_1c by statistically significant amounts, and increased the number of patients with HbA_1c levels below 7%

The safety results of Qternmet XR was consistent with each component medication’s known profile.

[email protected]

The Food and Drug Administration has approved Qternmet XR (dapagliflozin/saxagliptin/metformin) as an oral adjunct therapy to diet and exercise for the improvement of glycemic control in patients with type 2 diabetes, according to AstraZeneca.

Wikimedia Commons/FitzColinGerald/Creative Commons License

FDA approval is based on results from a pair of phase 3 trials that tested different combinations of dapagliflozin and saxagliptin in patients with inadequately controlled type 2 diabetes who were also receiving metformin over a 24-week period. In both trials, treatment with dapagliflozin/saxagliptin/metformin decreased hemoglobin A_1c by statistically significant amounts, and increased the number of patients with HbA_1c levels below 7%

The safety results of Qternmet XR was consistent with each component medication’s known profile.

[email protected]

The Food and Drug Administration has approved Qternmet XR (dapagliflozin/saxagliptin/metformin) as an oral adjunct therapy to diet and exercise for the improvement of glycemic control in patients with type 2 diabetes, according to AstraZeneca.

Wikimedia Commons/FitzColinGerald/Creative Commons License

FDA approval is based on results from a pair of phase 3 trials that tested different combinations of dapagliflozin and saxagliptin in patients with inadequately controlled type 2 diabetes who were also receiving metformin over a 24-week period. In both trials, treatment with dapagliflozin/saxagliptin/metformin decreased hemoglobin A_1c by statistically significant amounts, and increased the number of patients with HbA_1c levels below 7%

The safety results of Qternmet XR was consistent with each component medication’s known profile.

[email protected]

Bioimpedance spectroscopy may better identify lymphedema progression in women at risk for breast cancer–related lymphedema over the traditionally used method of monitoring arm circumference with a tape measure, according to results from an interim analysis of the PREVENT trial presented in a recent webcast from the annual meeting of the American Society of Breast Surgeons.

“Despite advances in breast-conserving surgery, improved radiation protocol, the advent of sentinel [node] biopsies and recent improvement in chemotherapy regimens, breast cancer–related lymphedema ... remains a major source of morbidity and concern in this patient population,” Sheila Ridner, PhD, RN, FAAN, professor of nursing at the Vanderbilt University School of Nursing in Nashville, Tenn., said in her presentation. “Because it is thought that early identification of swelling in the limbs coupled with a compression intervention may reduce the risk of patients developing full-blown clinical lymphedema, clinicians are proposing to use a prospective surveillance model to follow breast cancer survivors post surgery in order to assess limbs in a routine fashion and perhaps instigate preventative mechanisms early.”

The larger randomized controlled Prevention of Lymphedema Following Locoregional Treatment for Breast Cancer (PREVENT) trial enrolled 1,201 patients, and 200 patients overall have completed the full protocol. The researchers plan to follow patients for 3 years after surgery. In this interim analysis, Dr. Ridner and colleagues analyzed data from 508 patients at eight sites in the United States and four sites in Sydney who had stage I through stage III or ductal carcinoma in situ (DCIS) breast cancer and underwent mastectomy, taxane-based chemotherapy, or an axillary treatment such as axillary radiation, axillary lymph node dissection, or sentinel lymph nose biopsy with more than 6 nodes.

The patients were randomized to be measured using either traditional tape measurement or bioimpedance spectroscopy (BIS). Patients were moved to a prevention intervention if there was a change in baseline volume of 5% or greater but less than 10% in the tape measure group and change from baseline L-Dex measurement of 6.5 or greater in the BIS group, which consisted of wearing an arm compression sleeve and chest gauntlet for 12 hours a day over 4 weeks. After surgery, the patients were followed up at 3 months, 6 months, 12 months, 18 months, and 24 months, with optional follow-up visits at 15 months and 21 months. Progression to full lymphedema was defined as a 10% or greater change in pretreatment baseline measurements in the tape measure group.

Of the 508 patients analyzed, 10 patients had already progressed to full lymphedema, leaving 498 patients available for the interim analysis. There were 68 patients in the tape measure group (28.5%) and 41 patients in the BIS group (15.8%) who received the prevention intervention, and 10 patients in the tape measure group (14.7%) and 2 patients in the BIS group (4.9%) eventually progressed to full lymphedema. In the BIS group, there was a 10% absolute reduction and 67% relative reduction in lymphedema progression, compared with the tape measure group.

“We believe that the 10% absolute reduction is clinically significant for this patient population,” said Dr. Ridner. “We also believe that our interim results may support the concept of posttreatment surveillance using BIS for early detection of subclinical lymphedema coupled with early intervention as our preliminary data suggest this does have clinical advantages to the patient.”

The study was funded by ImpediMed. Dr. Ridner reports being the principal investigator for ImpediMed and Tactile Medical through work agreements contracted between the companies and her institution.

Bioimpedance spectroscopy may better identify lymphedema progression in women at risk for breast cancer–related lymphedema over the traditionally used method of monitoring arm circumference with a tape measure, according to results from an interim analysis of the PREVENT trial presented in a recent webcast from the annual meeting of the American Society of Breast Surgeons.

“Despite advances in breast-conserving surgery, improved radiation protocol, the advent of sentinel [node] biopsies and recent improvement in chemotherapy regimens, breast cancer–related lymphedema ... remains a major source of morbidity and concern in this patient population,” Sheila Ridner, PhD, RN, FAAN, professor of nursing at the Vanderbilt University School of Nursing in Nashville, Tenn., said in her presentation. “Because it is thought that early identification of swelling in the limbs coupled with a compression intervention may reduce the risk of patients developing full-blown clinical lymphedema, clinicians are proposing to use a prospective surveillance model to follow breast cancer survivors post surgery in order to assess limbs in a routine fashion and perhaps instigate preventative mechanisms early.”

The larger randomized controlled Prevention of Lymphedema Following Locoregional Treatment for Breast Cancer (PREVENT) trial enrolled 1,201 patients, and 200 patients overall have completed the full protocol. The researchers plan to follow patients for 3 years after surgery. In this interim analysis, Dr. Ridner and colleagues analyzed data from 508 patients at eight sites in the United States and four sites in Sydney who had stage I through stage III or ductal carcinoma in situ (DCIS) breast cancer and underwent mastectomy, taxane-based chemotherapy, or an axillary treatment such as axillary radiation, axillary lymph node dissection, or sentinel lymph nose biopsy with more than 6 nodes.

The patients were randomized to be measured using either traditional tape measurement or bioimpedance spectroscopy (BIS). Patients were moved to a prevention intervention if there was a change in baseline volume of 5% or greater but less than 10% in the tape measure group and change from baseline L-Dex measurement of 6.5 or greater in the BIS group, which consisted of wearing an arm compression sleeve and chest gauntlet for 12 hours a day over 4 weeks. After surgery, the patients were followed up at 3 months, 6 months, 12 months, 18 months, and 24 months, with optional follow-up visits at 15 months and 21 months. Progression to full lymphedema was defined as a 10% or greater change in pretreatment baseline measurements in the tape measure group.

Of the 508 patients analyzed, 10 patients had already progressed to full lymphedema, leaving 498 patients available for the interim analysis. There were 68 patients in the tape measure group (28.5%) and 41 patients in the BIS group (15.8%) who received the prevention intervention, and 10 patients in the tape measure group (14.7%) and 2 patients in the BIS group (4.9%) eventually progressed to full lymphedema. In the BIS group, there was a 10% absolute reduction and 67% relative reduction in lymphedema progression, compared with the tape measure group.

“We believe that the 10% absolute reduction is clinically significant for this patient population,” said Dr. Ridner. “We also believe that our interim results may support the concept of posttreatment surveillance using BIS for early detection of subclinical lymphedema coupled with early intervention as our preliminary data suggest this does have clinical advantages to the patient.”

The study was funded by ImpediMed. Dr. Ridner reports being the principal investigator for ImpediMed and Tactile Medical through work agreements contracted between the companies and her institution.

Bioimpedance spectroscopy may better identify lymphedema progression in women at risk for breast cancer–related lymphedema over the traditionally used method of monitoring arm circumference with a tape measure, according to results from an interim analysis of the PREVENT trial presented in a recent webcast from the annual meeting of the American Society of Breast Surgeons.

“Despite advances in breast-conserving surgery, improved radiation protocol, the advent of sentinel [node] biopsies and recent improvement in chemotherapy regimens, breast cancer–related lymphedema ... remains a major source of morbidity and concern in this patient population,” Sheila Ridner, PhD, RN, FAAN, professor of nursing at the Vanderbilt University School of Nursing in Nashville, Tenn., said in her presentation. “Because it is thought that early identification of swelling in the limbs coupled with a compression intervention may reduce the risk of patients developing full-blown clinical lymphedema, clinicians are proposing to use a prospective surveillance model to follow breast cancer survivors post surgery in order to assess limbs in a routine fashion and perhaps instigate preventative mechanisms early.”

The larger randomized controlled Prevention of Lymphedema Following Locoregional Treatment for Breast Cancer (PREVENT) trial enrolled 1,201 patients, and 200 patients overall have completed the full protocol. The researchers plan to follow patients for 3 years after surgery. In this interim analysis, Dr. Ridner and colleagues analyzed data from 508 patients at eight sites in the United States and four sites in Sydney who had stage I through stage III or ductal carcinoma in situ (DCIS) breast cancer and underwent mastectomy, taxane-based chemotherapy, or an axillary treatment such as axillary radiation, axillary lymph node dissection, or sentinel lymph nose biopsy with more than 6 nodes.

The patients were randomized to be measured using either traditional tape measurement or bioimpedance spectroscopy (BIS). Patients were moved to a prevention intervention if there was a change in baseline volume of 5% or greater but less than 10% in the tape measure group and change from baseline L-Dex measurement of 6.5 or greater in the BIS group, which consisted of wearing an arm compression sleeve and chest gauntlet for 12 hours a day over 4 weeks. After surgery, the patients were followed up at 3 months, 6 months, 12 months, 18 months, and 24 months, with optional follow-up visits at 15 months and 21 months. Progression to full lymphedema was defined as a 10% or greater change in pretreatment baseline measurements in the tape measure group.

Of the 508 patients analyzed, 10 patients had already progressed to full lymphedema, leaving 498 patients available for the interim analysis. There were 68 patients in the tape measure group (28.5%) and 41 patients in the BIS group (15.8%) who received the prevention intervention, and 10 patients in the tape measure group (14.7%) and 2 patients in the BIS group (4.9%) eventually progressed to full lymphedema. In the BIS group, there was a 10% absolute reduction and 67% relative reduction in lymphedema progression, compared with the tape measure group.

“We believe that the 10% absolute reduction is clinically significant for this patient population,” said Dr. Ridner. “We also believe that our interim results may support the concept of posttreatment surveillance using BIS for early detection of subclinical lymphedema coupled with early intervention as our preliminary data suggest this does have clinical advantages to the patient.”

The study was funded by ImpediMed. Dr. Ridner reports being the principal investigator for ImpediMed and Tactile Medical through work agreements contracted between the companies and her institution.