Article

Evidence summary

Time to delivery is shortened with combined therapy

Two recent high-quality meta-analyses investigated the effect of adding oxytocin to transcervical Foley balloon placement for cervical dilation. A network meta-analysis, including 30 RCTs (with 6465 pregnant patients), examined the efficacy of multiple combinations of cervical ripening methods.¹ A subset of 7 trials (n = 1313) compared oxytocin infusion with transcervical Foley (inflated to 30-60 mL) to Foley alone. Patients were at > 24 weeks’ gestation with a live fetus and undergoing elective or medical induction of labor; exclusion criteria were standard contraindications to vaginal delivery.

Compared to Foley alone, Foley plus oxytocin reduced both the time to the primary outcome of vaginal delivery (mean duration [MD] = –4.2 h; 95% CI, –1.9 to –6.5) and the time to overall (vaginal and cesarean) delivery (MD = –3.1 h; 95% CI, –1.5 to –4.6). There were no differences in rates of cesarean section, chorioamnionitis, epidural use, or neonatal intensive care unit admission. This analysis did not stratify by parity.¹

In a standard meta-analysis, researchers identified 6 RCTs (N = 1133) comparing transcervical Foley balloon and oxytocin to Foley balloon alone for cervical ripening in pregnant patients at > 23 weeks’ gestation (1 trial was limited to patients at > 37 weeks’ gestation).² Foley balloons were inflated with 30 to 60 mL saline, and oxytocin infusions started at 1 to 2 mU/min and were titrated up to 10 to 40 mU/min. Balloon time was usually 12 hours, but not always stated.

The authors found no statistically significant difference in cesarean rates (the primary outcome) between Foley plus oxytocin vs Foley alone (relative risk [RR] = 0.91; 95% CI, 0.76-1.1). Overall delivery within 12 hours was more likely with combined therapy (RR of remaining pregnant = 0.46; 95% CI, 0.34-0.63), but delivery at 24 hours was not (RR = 0.94; 95% CI, 0.92-1.05). However, in a sub-analysis by parity, nulliparous women who received combined therapy had higher overall delivery rates in 24 hours than did multiparous women (RR = 0.77; 95% CI, 0.62-0.97).²

Adding oxytocin may allow shorter transcervical balloon times

One recent RCT (N = 177) compared labor induction with oxytocin and a single trans-cervical balloon (Cook catheter with only the intrauterine balloon inflated) removed at either 6 or 12 hours.³ Patients were pregnant women (mean age, 31 years) with a term singleton vertex pregnancy, a Bishop score ≤ 6, and no contraindications to vaginal delivery. All patients received a balloon inflated to 60 mL with an oxytocin infusion (2-30 mU/min). The intervention group had the balloon removed at 6 hours, while the control group had it removed at 12 hours.

The mean Bishop score changed by 6 points in each group. Time to overall delivery (the primary outcome) was significantly shorter with 6 hours of balloon time than with 12 hours (19.2 vs 24.3 h; P < .04). Overall delivery within 24 hours was also significantly more likely in the 6-hour group (67.4% vs 47.4%; P < .01), although vaginal delivery in 24 hours did not change (74% vs 59%; P = .07). No differences were seen in cesarean delivery rates or maternal or neonatal morbidity rates.

A look at fixed-dose vs titrated oxytocin

Another RCT (N = 116) examined the effectiveness of cervical ripening using a Foley balloon plus either fixed-dose or titrated low-dose oxytocin.⁴ Patients (mean age, 26 years) had singleton pregnancies at ≥ 37 weeks’ gestation with a Bishop score < 6 and presented for induction of labor. Foley balloons were inflated to 30 mL, and patients received either a fixed oxytocin infusion of 2 mU/min or a titrated infusion starting at 1 mU/min, increasing by 2 mU/min every 30 minutes to a maximum of 20 mU/min.

Continue to: Thre was no statistically...

High-quality evidence shows that the addition of oxytocin to balloon cervical ripening shortens the time to delivery.

There was no statistically significant difference in median time from Foley placement to overall delivery (the primary outcome) between the fixed low-dose and incremental low-dose groups in either nulliparous women (24 vs 19 h; P = .18) or multiparous women (16 vs 12 h; P = .68). The authors acknowledged the study may have been underpowered to detect a true difference.

Recommendations from others

A 2009 Practice Bulletin from the American College of Obstetricians and Gynecologists (ACOG) recommended the Foley catheter as a reasonable and effective alternative to prostaglandins for cervical ripening and the induction of labor (based on good-quality evidence).⁵ The guideline stated that Foley catheter placement before oxytocin induction reduced both the duration of labor and risk of cesarean delivery, but that the use of oxytocin along with a Foley catheter did not appear to shorten the time to delivery.

Editor’s takeaway

High-quality evidence shows us that the addition of oxytocin to balloon cervical ripening shortens the time to delivery. This newer evidence may prompt an update to the 2009 ACOG statement.

Evidence summary

Time to delivery is shortened with combined therapy

Two recent high-quality meta-analyses investigated the effect of adding oxytocin to transcervical Foley balloon placement for cervical dilation. A network meta-analysis, including 30 RCTs (with 6465 pregnant patients), examined the efficacy of multiple combinations of cervical ripening methods.¹ A subset of 7 trials (n = 1313) compared oxytocin infusion with transcervical Foley (inflated to 30-60 mL) to Foley alone. Patients were at > 24 weeks’ gestation with a live fetus and undergoing elective or medical induction of labor; exclusion criteria were standard contraindications to vaginal delivery.

Compared to Foley alone, Foley plus oxytocin reduced both the time to the primary outcome of vaginal delivery (mean duration [MD] = –4.2 h; 95% CI, –1.9 to –6.5) and the time to overall (vaginal and cesarean) delivery (MD = –3.1 h; 95% CI, –1.5 to –4.6). There were no differences in rates of cesarean section, chorioamnionitis, epidural use, or neonatal intensive care unit admission. This analysis did not stratify by parity.¹

In a standard meta-analysis, researchers identified 6 RCTs (N = 1133) comparing transcervical Foley balloon and oxytocin to Foley balloon alone for cervical ripening in pregnant patients at > 23 weeks’ gestation (1 trial was limited to patients at > 37 weeks’ gestation).² Foley balloons were inflated with 30 to 60 mL saline, and oxytocin infusions started at 1 to 2 mU/min and were titrated up to 10 to 40 mU/min. Balloon time was usually 12 hours, but not always stated.

The authors found no statistically significant difference in cesarean rates (the primary outcome) between Foley plus oxytocin vs Foley alone (relative risk [RR] = 0.91; 95% CI, 0.76-1.1). Overall delivery within 12 hours was more likely with combined therapy (RR of remaining pregnant = 0.46; 95% CI, 0.34-0.63), but delivery at 24 hours was not (RR = 0.94; 95% CI, 0.92-1.05). However, in a sub-analysis by parity, nulliparous women who received combined therapy had higher overall delivery rates in 24 hours than did multiparous women (RR = 0.77; 95% CI, 0.62-0.97).²

Adding oxytocin may allow shorter transcervical balloon times

One recent RCT (N = 177) compared labor induction with oxytocin and a single trans-cervical balloon (Cook catheter with only the intrauterine balloon inflated) removed at either 6 or 12 hours.³ Patients were pregnant women (mean age, 31 years) with a term singleton vertex pregnancy, a Bishop score ≤ 6, and no contraindications to vaginal delivery. All patients received a balloon inflated to 60 mL with an oxytocin infusion (2-30 mU/min). The intervention group had the balloon removed at 6 hours, while the control group had it removed at 12 hours.

The mean Bishop score changed by 6 points in each group. Time to overall delivery (the primary outcome) was significantly shorter with 6 hours of balloon time than with 12 hours (19.2 vs 24.3 h; P < .04). Overall delivery within 24 hours was also significantly more likely in the 6-hour group (67.4% vs 47.4%; P < .01), although vaginal delivery in 24 hours did not change (74% vs 59%; P = .07). No differences were seen in cesarean delivery rates or maternal or neonatal morbidity rates.

A look at fixed-dose vs titrated oxytocin

Another RCT (N = 116) examined the effectiveness of cervical ripening using a Foley balloon plus either fixed-dose or titrated low-dose oxytocin.⁴ Patients (mean age, 26 years) had singleton pregnancies at ≥ 37 weeks’ gestation with a Bishop score < 6 and presented for induction of labor. Foley balloons were inflated to 30 mL, and patients received either a fixed oxytocin infusion of 2 mU/min or a titrated infusion starting at 1 mU/min, increasing by 2 mU/min every 30 minutes to a maximum of 20 mU/min.

Continue to: Thre was no statistically...

High-quality evidence shows that the addition of oxytocin to balloon cervical ripening shortens the time to delivery.

There was no statistically significant difference in median time from Foley placement to overall delivery (the primary outcome) between the fixed low-dose and incremental low-dose groups in either nulliparous women (24 vs 19 h; P = .18) or multiparous women (16 vs 12 h; P = .68). The authors acknowledged the study may have been underpowered to detect a true difference.

Recommendations from others

A 2009 Practice Bulletin from the American College of Obstetricians and Gynecologists (ACOG) recommended the Foley catheter as a reasonable and effective alternative to prostaglandins for cervical ripening and the induction of labor (based on good-quality evidence).⁵ The guideline stated that Foley catheter placement before oxytocin induction reduced both the duration of labor and risk of cesarean delivery, but that the use of oxytocin along with a Foley catheter did not appear to shorten the time to delivery.

Editor’s takeaway

High-quality evidence shows us that the addition of oxytocin to balloon cervical ripening shortens the time to delivery. This newer evidence may prompt an update to the 2009 ACOG statement.

Evidence summary

Time to delivery is shortened with combined therapy

Two recent high-quality meta-analyses investigated the effect of adding oxytocin to transcervical Foley balloon placement for cervical dilation. A network meta-analysis, including 30 RCTs (with 6465 pregnant patients), examined the efficacy of multiple combinations of cervical ripening methods.¹ A subset of 7 trials (n = 1313) compared oxytocin infusion with transcervical Foley (inflated to 30-60 mL) to Foley alone. Patients were at > 24 weeks’ gestation with a live fetus and undergoing elective or medical induction of labor; exclusion criteria were standard contraindications to vaginal delivery.

Compared to Foley alone, Foley plus oxytocin reduced both the time to the primary outcome of vaginal delivery (mean duration [MD] = –4.2 h; 95% CI, –1.9 to –6.5) and the time to overall (vaginal and cesarean) delivery (MD = –3.1 h; 95% CI, –1.5 to –4.6). There were no differences in rates of cesarean section, chorioamnionitis, epidural use, or neonatal intensive care unit admission. This analysis did not stratify by parity.¹

In a standard meta-analysis, researchers identified 6 RCTs (N = 1133) comparing transcervical Foley balloon and oxytocin to Foley balloon alone for cervical ripening in pregnant patients at > 23 weeks’ gestation (1 trial was limited to patients at > 37 weeks’ gestation).² Foley balloons were inflated with 30 to 60 mL saline, and oxytocin infusions started at 1 to 2 mU/min and were titrated up to 10 to 40 mU/min. Balloon time was usually 12 hours, but not always stated.

The authors found no statistically significant difference in cesarean rates (the primary outcome) between Foley plus oxytocin vs Foley alone (relative risk [RR] = 0.91; 95% CI, 0.76-1.1). Overall delivery within 12 hours was more likely with combined therapy (RR of remaining pregnant = 0.46; 95% CI, 0.34-0.63), but delivery at 24 hours was not (RR = 0.94; 95% CI, 0.92-1.05). However, in a sub-analysis by parity, nulliparous women who received combined therapy had higher overall delivery rates in 24 hours than did multiparous women (RR = 0.77; 95% CI, 0.62-0.97).²

Adding oxytocin may allow shorter transcervical balloon times

One recent RCT (N = 177) compared labor induction with oxytocin and a single trans-cervical balloon (Cook catheter with only the intrauterine balloon inflated) removed at either 6 or 12 hours.³ Patients were pregnant women (mean age, 31 years) with a term singleton vertex pregnancy, a Bishop score ≤ 6, and no contraindications to vaginal delivery. All patients received a balloon inflated to 60 mL with an oxytocin infusion (2-30 mU/min). The intervention group had the balloon removed at 6 hours, while the control group had it removed at 12 hours.

The mean Bishop score changed by 6 points in each group. Time to overall delivery (the primary outcome) was significantly shorter with 6 hours of balloon time than with 12 hours (19.2 vs 24.3 h; P < .04). Overall delivery within 24 hours was also significantly more likely in the 6-hour group (67.4% vs 47.4%; P < .01), although vaginal delivery in 24 hours did not change (74% vs 59%; P = .07). No differences were seen in cesarean delivery rates or maternal or neonatal morbidity rates.

A look at fixed-dose vs titrated oxytocin

Another RCT (N = 116) examined the effectiveness of cervical ripening using a Foley balloon plus either fixed-dose or titrated low-dose oxytocin.⁴ Patients (mean age, 26 years) had singleton pregnancies at ≥ 37 weeks’ gestation with a Bishop score < 6 and presented for induction of labor. Foley balloons were inflated to 30 mL, and patients received either a fixed oxytocin infusion of 2 mU/min or a titrated infusion starting at 1 mU/min, increasing by 2 mU/min every 30 minutes to a maximum of 20 mU/min.

Continue to: Thre was no statistically...

High-quality evidence shows that the addition of oxytocin to balloon cervical ripening shortens the time to delivery.

There was no statistically significant difference in median time from Foley placement to overall delivery (the primary outcome) between the fixed low-dose and incremental low-dose groups in either nulliparous women (24 vs 19 h; P = .18) or multiparous women (16 vs 12 h; P = .68). The authors acknowledged the study may have been underpowered to detect a true difference.

Recommendations from others

A 2009 Practice Bulletin from the American College of Obstetricians and Gynecologists (ACOG) recommended the Foley catheter as a reasonable and effective alternative to prostaglandins for cervical ripening and the induction of labor (based on good-quality evidence).⁵ The guideline stated that Foley catheter placement before oxytocin induction reduced both the duration of labor and risk of cesarean delivery, but that the use of oxytocin along with a Foley catheter did not appear to shorten the time to delivery.

Editor’s takeaway

High-quality evidence shows us that the addition of oxytocin to balloon cervical ripening shortens the time to delivery. This newer evidence may prompt an update to the 2009 ACOG statement.

A 23-year-old woman with systemic lupus erythematosus (SLE) and a history of poor adherence to recommended treatment presented with a widespread pruritic rash and diffuse hair loss. The rash had rapidly progressed following sun exposure during the summer. The patient cited her mental health status (anxiety, depression), socioeconomic factors, and challenges with prescription insurance coverage as reasons for nonadherence to treatment.

Clinical examination revealed diffuse scarring alopecia and abnormal pigmentation of the scalp (FIGURE 1A), as well as large, red-brown, scaly, atrophic plaques on the face, ears, extremities, back, and buttocks (FIGURES 1B and 1C).

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

The clinical features of our patient were most consistent with generalized chronic cutaneous lupus erythematosus (CCLE), which is 1 of 3 subtypes of cutaneous lupus erythematosus (CLE). The other 2 are acute and subacute cutaneous lupus erythematosus (ACLE and SCLE, respectively). CCLE is further divided into 3 distinct entities: discoid lupus erythematosus (DLE), chilblain lupus erythematosus, and lupus erythematosus panniculitis.

A negative ANA should not rule out the possibility of cutaneous lupus erythematosus.

Distinguishing between the different forms of cutaneous lupus can be challenging; diagnosis is based on differences in clinical features and duration of skin changes, as well as biopsy and lab results.¹ The clinical features of our patient were most consistent with DLE, based on the scarring alopecia with scaly atrophic plaques, dyspigmentation, and exacerbation following sun exposure.

DLE is the most common form of CCLE and frequently manifests in a localized, photosensitive distribution involving the scalp, ears, and/or face.² Less commonly, it can demonstrate a more generalized distribution involving the trunk and/or extremities (reported incidence of 1.04 per 100,000 people).³ Longstanding DLE lesions commonly exhibit scarring and dyspigmentation. DLE occurs in approximately 15% to 30% of SLE patients,⁴ whereas about 10% of patients with DLE will progress to SLE.³

Positive antinuclear antibodies (ANA) are found in 54% of patients with CCLE, compared to 74% and 81% of patients with SCLE and ACLE, respectively.⁵ Thus, a negative ANA should not rule out the possibility of CLE.

Comprehensive lab work and biopsy could expose a systemic origin

While our patient already had a diagnosis of SLE, many patients will present with no prior history of autoimmune connective tissue disease, and, in that case, the objective should be to confirm the diagnosis and evaluate for systemic involvement. This includes a thorough review of systems; skin biopsy; complete blood count; liver function tests; urinalysis; and measurement of creatinine, inflammatory markers, ANA, extractable nuclear antigens, double-stranded DNA, complement levels (C3, C4, total), and antiphospholipid antibodies.⁶

Continue to: Biopsy

Biopsy features of DLE include vacuolar interface dermatitis, basement membrane zone thickening, follicular plugging, superficial and deep perivascular and periadnexal lymphohistiocytic inflammation with plasma cells, and increased mucin deposition. Direct immunofluorescence biopsy may show a continuous granular immunoglobulin (Ig) G/IgA/IgM and C3 band at the basement membrane zone.

Abnormal serologic tests may support the diagnosis of SLE based on American College of Rheumatology criteria and could suggest additional organ involvement or associated conditions, such as lupus nephritis or antiphospholipid syndrome (respectively). Currently, no clear consensus exists on monitoring patients with cutaneous lupus for systemic disease.

A gamut of skin-changing conditions should be considered

The differential diagnosis in this case includes SCLE, dermatitis, tinea corporis, cutaneous drug eruptions, and graft-versus-host disease (GVHD).

SCLE classically manifests with annular or psoriasiform lesions on the sun-exposed areas of the upper trunk (eg, the chest, neck, and upper extremities), while the central face and scalp are typically spared. Differentiating between generalized DLE and SCLE may be the most difficult, given similarities in the associated skin changes.

Dermatitis (atopic or contact) manifests as pruritic erythematous eczematous plaques, most commonly involving the flexural areas in atopic dermatitis and an exposure-dependent distribution pattern in contact dermatitis. The patient may have a history of atopy.

Continue to: Tinea corporis

Tinea corporis will manifest with annular scaly patches or plaques and may demonstrate erythematous papules around hair follicles in Majocchi granuloma. A positive potassium hydroxide exam demonstrating fungal hyphae confirms the diagnosis.

Cutaneous drug eruptions can have various morphologies and timing of onset. Certain photosensitive drug reactions can be triggered or exacerbated with sun exposure. Therefore, it is necessary to obtain a thorough medication history, including any new medications that were started within the past 4 to 6 weeks, although onset can be delayed beyond this timeframe.

GVHD is a complication that more commonly follows allogeneic hematopoietic stem cell transplants, although it may be seen following solid-organ transplantation or transfusion of nonirradiated blood. Chronic GVHD has an onset ≥ 100 days after transplant and is divided into nonsclerotic (lichenoid, atopic dermatitis-like, psoriasiform, poikilodermatous) and sclerotic morphologies.

Successful Tx requires adherence but may not prevent flare-ups

First-line treatment options for severe and widespread skin manifestations of CLE include photoprotection, smoking cessation, topical corticosteroids, hydroxychloroquine, and systemic corticosteroids. Second-line treatments include chloroquine, methotrexate, or mycophenolate mofetil; thalidomide or lenalidomide may be considered for patients with refractory disease.^7,8

With successful treatment and photoprotection, patients may achieve significant skin clearing. Occasional flares, especially during warmer months, may occur if they are not diligent about photoprotection. Systemic treatments will also improve the patient’s systemic symptoms if the patient has concomitant SLE.

Our patient was advised to use topical steroids and to restart hydroxychloroquine 300 mg/d and mycophenolate mofetil 1000 mg/d (a regimen with which she had previously been nonadherent). The patient followed up with her family physician for assessment of her other medical issues. No new interventions for her mental health were initiated during this visit, as the severity of her depression was considered mild. She was referred to a case manager to navigate multiple medical appointments and prescription insurance coverage issues. The patient’s dose of mycophenolate mofetil was increased gradually to 3 g/d, and the patient experienced improvement in both her cutaneous lesions and systemic symptoms.

A 23-year-old woman with systemic lupus erythematosus (SLE) and a history of poor adherence to recommended treatment presented with a widespread pruritic rash and diffuse hair loss. The rash had rapidly progressed following sun exposure during the summer. The patient cited her mental health status (anxiety, depression), socioeconomic factors, and challenges with prescription insurance coverage as reasons for nonadherence to treatment.

Clinical examination revealed diffuse scarring alopecia and abnormal pigmentation of the scalp (FIGURE 1A), as well as large, red-brown, scaly, atrophic plaques on the face, ears, extremities, back, and buttocks (FIGURES 1B and 1C).

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

The clinical features of our patient were most consistent with generalized chronic cutaneous lupus erythematosus (CCLE), which is 1 of 3 subtypes of cutaneous lupus erythematosus (CLE). The other 2 are acute and subacute cutaneous lupus erythematosus (ACLE and SCLE, respectively). CCLE is further divided into 3 distinct entities: discoid lupus erythematosus (DLE), chilblain lupus erythematosus, and lupus erythematosus panniculitis.

A negative ANA should not rule out the possibility of cutaneous lupus erythematosus.

Distinguishing between the different forms of cutaneous lupus can be challenging; diagnosis is based on differences in clinical features and duration of skin changes, as well as biopsy and lab results.¹ The clinical features of our patient were most consistent with DLE, based on the scarring alopecia with scaly atrophic plaques, dyspigmentation, and exacerbation following sun exposure.

DLE is the most common form of CCLE and frequently manifests in a localized, photosensitive distribution involving the scalp, ears, and/or face.² Less commonly, it can demonstrate a more generalized distribution involving the trunk and/or extremities (reported incidence of 1.04 per 100,000 people).³ Longstanding DLE lesions commonly exhibit scarring and dyspigmentation. DLE occurs in approximately 15% to 30% of SLE patients,⁴ whereas about 10% of patients with DLE will progress to SLE.³

Positive antinuclear antibodies (ANA) are found in 54% of patients with CCLE, compared to 74% and 81% of patients with SCLE and ACLE, respectively.⁵ Thus, a negative ANA should not rule out the possibility of CLE.

Comprehensive lab work and biopsy could expose a systemic origin

While our patient already had a diagnosis of SLE, many patients will present with no prior history of autoimmune connective tissue disease, and, in that case, the objective should be to confirm the diagnosis and evaluate for systemic involvement. This includes a thorough review of systems; skin biopsy; complete blood count; liver function tests; urinalysis; and measurement of creatinine, inflammatory markers, ANA, extractable nuclear antigens, double-stranded DNA, complement levels (C3, C4, total), and antiphospholipid antibodies.⁶

Continue to: Biopsy

Biopsy features of DLE include vacuolar interface dermatitis, basement membrane zone thickening, follicular plugging, superficial and deep perivascular and periadnexal lymphohistiocytic inflammation with plasma cells, and increased mucin deposition. Direct immunofluorescence biopsy may show a continuous granular immunoglobulin (Ig) G/IgA/IgM and C3 band at the basement membrane zone.

Abnormal serologic tests may support the diagnosis of SLE based on American College of Rheumatology criteria and could suggest additional organ involvement or associated conditions, such as lupus nephritis or antiphospholipid syndrome (respectively). Currently, no clear consensus exists on monitoring patients with cutaneous lupus for systemic disease.

A gamut of skin-changing conditions should be considered

The differential diagnosis in this case includes SCLE, dermatitis, tinea corporis, cutaneous drug eruptions, and graft-versus-host disease (GVHD).

SCLE classically manifests with annular or psoriasiform lesions on the sun-exposed areas of the upper trunk (eg, the chest, neck, and upper extremities), while the central face and scalp are typically spared. Differentiating between generalized DLE and SCLE may be the most difficult, given similarities in the associated skin changes.

Dermatitis (atopic or contact) manifests as pruritic erythematous eczematous plaques, most commonly involving the flexural areas in atopic dermatitis and an exposure-dependent distribution pattern in contact dermatitis. The patient may have a history of atopy.

Continue to: Tinea corporis

Tinea corporis will manifest with annular scaly patches or plaques and may demonstrate erythematous papules around hair follicles in Majocchi granuloma. A positive potassium hydroxide exam demonstrating fungal hyphae confirms the diagnosis.

Cutaneous drug eruptions can have various morphologies and timing of onset. Certain photosensitive drug reactions can be triggered or exacerbated with sun exposure. Therefore, it is necessary to obtain a thorough medication history, including any new medications that were started within the past 4 to 6 weeks, although onset can be delayed beyond this timeframe.

GVHD is a complication that more commonly follows allogeneic hematopoietic stem cell transplants, although it may be seen following solid-organ transplantation or transfusion of nonirradiated blood. Chronic GVHD has an onset ≥ 100 days after transplant and is divided into nonsclerotic (lichenoid, atopic dermatitis-like, psoriasiform, poikilodermatous) and sclerotic morphologies.

Successful Tx requires adherence but may not prevent flare-ups

First-line treatment options for severe and widespread skin manifestations of CLE include photoprotection, smoking cessation, topical corticosteroids, hydroxychloroquine, and systemic corticosteroids. Second-line treatments include chloroquine, methotrexate, or mycophenolate mofetil; thalidomide or lenalidomide may be considered for patients with refractory disease.^7,8

With successful treatment and photoprotection, patients may achieve significant skin clearing. Occasional flares, especially during warmer months, may occur if they are not diligent about photoprotection. Systemic treatments will also improve the patient’s systemic symptoms if the patient has concomitant SLE.

Our patient was advised to use topical steroids and to restart hydroxychloroquine 300 mg/d and mycophenolate mofetil 1000 mg/d (a regimen with which she had previously been nonadherent). The patient followed up with her family physician for assessment of her other medical issues. No new interventions for her mental health were initiated during this visit, as the severity of her depression was considered mild. She was referred to a case manager to navigate multiple medical appointments and prescription insurance coverage issues. The patient’s dose of mycophenolate mofetil was increased gradually to 3 g/d, and the patient experienced improvement in both her cutaneous lesions and systemic symptoms.

A 23-year-old woman with systemic lupus erythematosus (SLE) and a history of poor adherence to recommended treatment presented with a widespread pruritic rash and diffuse hair loss. The rash had rapidly progressed following sun exposure during the summer. The patient cited her mental health status (anxiety, depression), socioeconomic factors, and challenges with prescription insurance coverage as reasons for nonadherence to treatment.

Clinical examination revealed diffuse scarring alopecia and abnormal pigmentation of the scalp (FIGURE 1A), as well as large, red-brown, scaly, atrophic plaques on the face, ears, extremities, back, and buttocks (FIGURES 1B and 1C).

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

The clinical features of our patient were most consistent with generalized chronic cutaneous lupus erythematosus (CCLE), which is 1 of 3 subtypes of cutaneous lupus erythematosus (CLE). The other 2 are acute and subacute cutaneous lupus erythematosus (ACLE and SCLE, respectively). CCLE is further divided into 3 distinct entities: discoid lupus erythematosus (DLE), chilblain lupus erythematosus, and lupus erythematosus panniculitis.

A negative ANA should not rule out the possibility of cutaneous lupus erythematosus.

Distinguishing between the different forms of cutaneous lupus can be challenging; diagnosis is based on differences in clinical features and duration of skin changes, as well as biopsy and lab results.¹ The clinical features of our patient were most consistent with DLE, based on the scarring alopecia with scaly atrophic plaques, dyspigmentation, and exacerbation following sun exposure.

DLE is the most common form of CCLE and frequently manifests in a localized, photosensitive distribution involving the scalp, ears, and/or face.² Less commonly, it can demonstrate a more generalized distribution involving the trunk and/or extremities (reported incidence of 1.04 per 100,000 people).³ Longstanding DLE lesions commonly exhibit scarring and dyspigmentation. DLE occurs in approximately 15% to 30% of SLE patients,⁴ whereas about 10% of patients with DLE will progress to SLE.³

Positive antinuclear antibodies (ANA) are found in 54% of patients with CCLE, compared to 74% and 81% of patients with SCLE and ACLE, respectively.⁵ Thus, a negative ANA should not rule out the possibility of CLE.

Comprehensive lab work and biopsy could expose a systemic origin

While our patient already had a diagnosis of SLE, many patients will present with no prior history of autoimmune connective tissue disease, and, in that case, the objective should be to confirm the diagnosis and evaluate for systemic involvement. This includes a thorough review of systems; skin biopsy; complete blood count; liver function tests; urinalysis; and measurement of creatinine, inflammatory markers, ANA, extractable nuclear antigens, double-stranded DNA, complement levels (C3, C4, total), and antiphospholipid antibodies.⁶

Continue to: Biopsy

Biopsy features of DLE include vacuolar interface dermatitis, basement membrane zone thickening, follicular plugging, superficial and deep perivascular and periadnexal lymphohistiocytic inflammation with plasma cells, and increased mucin deposition. Direct immunofluorescence biopsy may show a continuous granular immunoglobulin (Ig) G/IgA/IgM and C3 band at the basement membrane zone.

Abnormal serologic tests may support the diagnosis of SLE based on American College of Rheumatology criteria and could suggest additional organ involvement or associated conditions, such as lupus nephritis or antiphospholipid syndrome (respectively). Currently, no clear consensus exists on monitoring patients with cutaneous lupus for systemic disease.

A gamut of skin-changing conditions should be considered

The differential diagnosis in this case includes SCLE, dermatitis, tinea corporis, cutaneous drug eruptions, and graft-versus-host disease (GVHD).

SCLE classically manifests with annular or psoriasiform lesions on the sun-exposed areas of the upper trunk (eg, the chest, neck, and upper extremities), while the central face and scalp are typically spared. Differentiating between generalized DLE and SCLE may be the most difficult, given similarities in the associated skin changes.

Dermatitis (atopic or contact) manifests as pruritic erythematous eczematous plaques, most commonly involving the flexural areas in atopic dermatitis and an exposure-dependent distribution pattern in contact dermatitis. The patient may have a history of atopy.

Continue to: Tinea corporis

Tinea corporis will manifest with annular scaly patches or plaques and may demonstrate erythematous papules around hair follicles in Majocchi granuloma. A positive potassium hydroxide exam demonstrating fungal hyphae confirms the diagnosis.

Cutaneous drug eruptions can have various morphologies and timing of onset. Certain photosensitive drug reactions can be triggered or exacerbated with sun exposure. Therefore, it is necessary to obtain a thorough medication history, including any new medications that were started within the past 4 to 6 weeks, although onset can be delayed beyond this timeframe.

GVHD is a complication that more commonly follows allogeneic hematopoietic stem cell transplants, although it may be seen following solid-organ transplantation or transfusion of nonirradiated blood. Chronic GVHD has an onset ≥ 100 days after transplant and is divided into nonsclerotic (lichenoid, atopic dermatitis-like, psoriasiform, poikilodermatous) and sclerotic morphologies.

Successful Tx requires adherence but may not prevent flare-ups

First-line treatment options for severe and widespread skin manifestations of CLE include photoprotection, smoking cessation, topical corticosteroids, hydroxychloroquine, and systemic corticosteroids. Second-line treatments include chloroquine, methotrexate, or mycophenolate mofetil; thalidomide or lenalidomide may be considered for patients with refractory disease.^7,8

With successful treatment and photoprotection, patients may achieve significant skin clearing. Occasional flares, especially during warmer months, may occur if they are not diligent about photoprotection. Systemic treatments will also improve the patient’s systemic symptoms if the patient has concomitant SLE.

Our patient was advised to use topical steroids and to restart hydroxychloroquine 300 mg/d and mycophenolate mofetil 1000 mg/d (a regimen with which she had previously been nonadherent). The patient followed up with her family physician for assessment of her other medical issues. No new interventions for her mental health were initiated during this visit, as the severity of her depression was considered mild. She was referred to a case manager to navigate multiple medical appointments and prescription insurance coverage issues. The patient’s dose of mycophenolate mofetil was increased gradually to 3 g/d, and the patient experienced improvement in both her cutaneous lesions and systemic symptoms.

Dyspareunia is persistent or recurrent pain before, during, or after sexual contact and is not limited to cisgender individuals or vaginal intercourse.^1-3 With a prevalence as high as 45% in the United States,^2-5 it is one of the most common complaints in gynecologic practices.^5,6

Causes and contributing factors

There are many possible causes of dyspareunia.^2,4,6 While some patients have a single cause, most cases are complex, with multiple overlapping causes and maintaining factors.^4,6 Identifying each contributing factor can help you appropriately address all components.

Physical conditions. The range of physical contributors to dyspareunia includes inflammatory processes, structural abnormalities, musculoskeletal dysfunctions, pelvic organ disorders, injuries, iatrogenic effects, infections, allergic reactions, sensitization, hormonal changes, medication effects, adhesions, autoimmune disorders, and other pain syndromes (TABLE 1^2-4,6-11).

Inadequate arousal. One of the primary causes of pain during vaginal penetration is inadequate arousal and lubrication.^1,2,9-11 Arousal is the phase of the sexual response cycle that leads to genital tumescence and prepares the genitals for sexual contact through penile/clitoral erection, vaginal engorgement, and lubrication, which prevents pain and enhances pleasurable sensation.^9-11

While some physical conditions can lead to an inability to lubricate, the most common causes of inadequate lubrication are psychosocial-behavioral, wherein patients have the same physical ability to lubricate as patients without genital pain but do not progress through the arousal phase.^9-11 Behavioral factors such as inadequate or ineffective foreplay can fail to produce engorgement and lubrication, while psychosocial factors such as low attraction to partner, relationship stressors, anxiety, or low self-esteem can have an inhibitory effect on sexual arousal.^1,2,9-11 Psychosocial and behavioral factors may also be maintaining factors or consequences of dyspareunia, and need to be assessed and treated.^1,2,9-11

Psychological trauma. Exposure to psychological traumas and the development of posttraumatic stress disorder (PTSD) have been linked with the development of pain disorders in general and dyspareunia specifically. Most patients seeking treatment for chronic pain disorders have a history of physical or sexual abuse.¹² Changes in physiologic processes (eg, neurochemical, endocrine) that occur with PTSD interfere with the sexual response cycle, and sexual traumas specifically have been linked with pelvic floor dysfunction.^13,14 Additionally, when PTSD is caused by a sexual trauma, even consensual sexual encounters can trigger flashbacks, intrusive memories, hyperarousal, and muscle tension that interfere with the sexual response cycle and contribute to genital pain.¹³

Vaginismus is both a physiologic and psychological contributor to dyspareunia.^1,2,4 Patients experiencing pain can develop anxiety about repeated pain and involuntarily contract their pelvic muscles, thereby creating more pain, increasing anxiety, decreasing lubrication, and causing pelvic floor dysfunction.^1-4,6 Consequently, all patients with dyspareunia should be assessed and continually monitored for symptoms of vaginismus.

Continue to: Anxiety

Anxiety. As with other pain disorders, anxiety develops around pain triggers.^10,15 When expecting sexual activity, patients can experience extreme worry and panic attacks.^10,15,16 The distress of sexual encounters can interfere with physiologic arousal and sexual desire, impacting all phases of the sexual response cycle.^1,2

Relationship issues. Difficulty engaging in or avoidance of sexual activity can interfere with romantic relationships.^2,10,16 Severe pain or vaginismus contractions can prevent penetration, leading to unconsummated marriages and an inability to conceive through intercourse.¹⁰ The distress surrounding sexual encounters can precipitate erectile dysfunction in male partners, or partners may continue to demand sexual encounters despite the patient’s pain, further impacting the relationship and heightening sexual distress.¹⁰ These stressors have led to relationships ending, patients reluctantly agreeing to nonmonogamy to appease their partners, and patients avoiding relationships altogether.^10,16

Devalued self-image. Difficulties with sexuality and relationships impact the self-image of patients with dyspareunia. Diminished self-image may include feeling “inadequate” as a woman and as a sexual partner, or feeling like a “failure.”¹⁶ Women with dyspareunia often have more distress related to their body image, physical appearance, and genital self-image than do women without genital pain.¹⁷ Feeling resentment toward their body, or feeling “ugly,” embarrassed, shamed, “broken,” and “useless” also contribute to increased depressive symptoms found in patients with dyspareunia.^16,18

Making the diagnosis

Most patients do not report symptoms unless directly asked^2,7; therefore, it is recommended that all patients be screened as a part of an initial intake and before any genital exam (TABLE 2^{2-4,6,7,9,11,19,20}).^4,7,21 If this screen is positive, a separate appointment may be needed for a thorough evaluation and before any attempt is made at a genital exam.^4,7

Items to include in the clinical interview

Given the range of possible causes of dyspareunia and its contributing factors and symptoms, a thorough clinical interview is essential. Begin with a review of the patient’s complete medical and surgical history to identify possible known contributors to genital pain.⁴ Pregnancy history is of particular importance as the prevalence of postpartum dyspareunia is 35%, with risk being greater for patients who experienced dyspareunia symptoms before pregnancy.²²

Consider using a measure such as the Female Sexual Function Index or the McGill Pain Questionnaire to help patients more thoroughly describe their symptoms.

Knowing the location and quality of pain is important for differentiating between possible diagnoses, as is specifying dyspareunia as lifelong or acquired, superficial or deep, and primary or secondary.^1-4,6 Confirm the specific location(s) of pain—eg, at the introitus, in the vestibule, on the labia, in the perineum, or near the clitoris.^2,4,6 A diagram or model may be needed to help patients to localize pain.⁴

To help narrow the differential, include the following elements in your assessment: pain quality, timing (eg, initial onset, episode onset, episode duration, situational triggers), alleviating factors, symptoms in surrounding structures (eg, bladder, bowel, muscles, bones), sexual history, other areas of sexual functioning, history of psychological trauma, relationship effects, and mental health (TABLE 2^{2-4,6,7,9,11,19,20} and Table 3^23-28). Screening for a history of sexual trauma is particularly important, as a recent systematic review and meta-analysis found that women with a history of sexual assault had a 42% higher risk of gynecologic problems overall, a 74% higher risk of dyspareunia, and a 71% higher risk of vaginismus than women without a history of sexual assault.²⁹ Using measures such as the Female Sexual Function Index or the McGill Pain Questionnaire can help patients more thoroughly describe their symptoms (TABLE 3^23-28).³

Continue to: Guidelines for the physical exam

Before the exam, ensure the patient has not used any topical genital treatment in the past 2 weeks that may interfere with sensitivity to the exam.⁴ To decrease patients’ anxiety about the exam, remind them that they can stop the exam at any time.⁷ Also consider offering the use of a mirror to better pinpoint the location of pain, and to possibly help the patient learn more about her anatomy.^2,7

Begin the exam by palpating surrounding areas that may be involved in pain, including the abdomen and musculoskeletal features.^3,6,19 Next visually inspect the external genitalia for lesions, abrasions, discoloration, erythema, or other abnormal findings.^2,3,6 Ask the patient for permission before contacting the genitals. Because the labia may be a site of pain, apply gentle pressure in retracting it to fully examine the vestibule.^6,7 Contraction of the pelvic floor muscles during approach or initial palpation could signal possible vaginismus.⁴

After visual inspection of external genitalia, use a cotton swab to map the vulva and vestibule in a clockwise fashion to precisely identify any painful locations.^2-4,6 If the patient’s history of pain has been intermittent, it’s possible that the cotton swab will not elicit pain on the day of the initial exam, but it may on other days.⁴

Begin the internal exam by inserting a single finger into the first inch of the vagina and have the patient squeeze and release to assess tenderness, muscle tightness, and control.^2,6 Advance the finger further into the vagina and palpate clockwise, examining the levator muscles, obturator muscles, rectum, urethra, and bladder for abnormal tightness or reproduction of pain.^2,4,6 Complete a bimanual exam to evaluate the pelvic organs and adnexa.^2,4 If indicated, a more thorough evaluation of pelvic floor musculature can be performed by a physical therapist or gynecologist who specializes in pelvic pain.^2-4

If the patient consents to further evaluation, consider using a small speculum, advanced slowly, for further internal examination, noting any lesions, abrasions, discharge, ectropion, or tenderness.^2-4,7 A rectal exam may also be needed in cases of deep dyspareunia.⁶ Initial work-up may include a potassium hydroxide wet prep, sexually transmitted infection testing, and pelvic ultrasound.^2,4 In some cases, laparoscopy or biopsy may be needed.^2,4

Treatments for common causes

Treatment often begins with education about anatomy, to help patients communicate about symptoms and engage more fully in their care.³ Additional education may be needed on genital functioning and the necessity of adequate stimulation and lubrication prior to penetration.^1,2,9-11 A discussion of treatments for the wide range of possible causes of dyspareunia is outside the scope of this article. However, some basic behavioral changes may help patients address some of the more common contributing factors.

A recent systematic review and meta-analysis found that women with a history of sexual assault had a 74% higher risk of dyspareunia than women without such a history.

For example, if vaginal infection is suspected, advise patients to discontinue the use of harsh soaps, known vaginal irritants (eg, perfumed products, bath additives), and douches.³ Recommend using only ­preservative- and alcohol-free lubricants for sexual contact, and avoiding lubricants with added functions (eg, warming).³ It’s worth noting that avoidance of tight clothing and thong underwear due to possible risk for infections may not be necessary. A recent study found that women who frequently wore thong underwear (more than half of the time) were no more likely to develop urinary tract infections, yeast vaginitis, or bacterial vaginosis than those who avoid such items.³⁰ However, noncotton underwear fabric, rather than tightness, was associated with yeast vaginitis³⁰; therefore, patients may want to consider using only breathable underwear.³

Continue to: Medication

Medication. Medication may be used to treat the underlying contributing conditions or the symptom of pain directly. Some common options are particularly important for patients whose dyspareunia does not have an identifiable cause. These medications include anti-inflammatory agents, topical anesthetics, tricyclic antidepressants, and hormonal treatments.^2-4 Since effectiveness varies based on subtypes of pain, select a medication according to the location, timing, and hypothesized mechanism of pain.^3,31,32

Medication for deep pain. A meta-analysis and systematic review found that patients with some types of chronic pelvic pain with pain deep in the vagina or pelvis experienced greater than 50% reduction in pain using medroxyprogesterone acetate compared with placebo.³³ Other treatments for deep pain depend on physical exam findings.

Medication for superficial pain. Many remedies have been tried, with at least 26 different treatments for vulvodynia pain alone.¹⁶ Only some of these treatments have supporting evidence. For patients with vulvar pain, an intent-to-treat RCT found that patients using a topical steroid experienced a 23% reduction in pain from pre-treatment to 6-month follow-up.³²

Surgery is also effective for vulvar pain.^34,35 For provoked vestibulodynia (in which pain is localized to the vestibule and triggered by contact with the vulva), or vulvar vestibulitis, RCTs have found that vestibulectomy has stronger effects on pain than other treatments,^31,35 with a 53% reduction in pain during intercourse and a 70% reduction in vestibular pain overall.³⁵ However, while vestibulectomy is effective for provoked vestibulodynia, it is not recommended for generalized vulvodynia, in which pain is diffuse across the vulva and occurs without vulvar contact.³⁴

Unsupported treatments. A number of other treatments have not yet been found effective. Although lidocaine for vulvar pain is often used, RCTs have not found any significant reduction in symptoms, and a ­double-blind RCT found that lidocaine ointment actually performed worse than placebo.^31,34 Similarly, oral tricyclics have not been found to decrease vulvar pain more than placebo in double-blind studies.^31,34 Furthermore, a meta-analysis of RCTs comparing treatments with placebo for vestibular pain found no significant decrease in dyspareunia for topical conjugated estrogen, topical lidocaine, oral desipramine, oral desipramine with topical lidocaine, laser therapy, or transcranial direct current.³²

Tx risks to consider. Risks and benefits of dyspareunia treatment options should be thoroughly weighed and discussed with the patient.^2-4 Vestibulectomy, despite reducing pain for many patients, has led to increased pain for 9% of patients who underwent the procedure.³⁵ Topical treatments may lead to allergic reactions, inflammation, and worsening of symptoms,⁴ and hormonal treatments have been found to increase the risk of weight gain and bloating and are not appropriate for patients trying to conceive.³³

Coordinate care with other providers

While medications and surgery can reduce pain, they have not been shown to improve other aspects of sexual functioning such as sexual satisfaction, frequency of sexual intercourse, or overall sense of sexual functioning.³⁵ Additionally, pain reduction does not address muscle tension, anxiety, self-­esteem, and relationship problems. As a result, a multidisciplinary approach is generally needed.^3,4,32,33

Continue to: Physical therapists

Physical therapists. Pelvic floor physical therapists are often members of the dyspareunia treatment team and can provide a thorough evaluation and treatment of pelvic floor disorders.^2-4 An RCT with intent-to-treat analysis found that pain was reduced by 71% following pelvic floor physical therapy.³⁶ Another RCT found that 90% of patients reported a clinically meaningful decrease in pain with pelvic floor physical therapy.³⁷ In addition to addressing pain, pelvic floor physical therapy has also been found to improve sexual functioning, sexual satisfaction, distress, and patient perception of improvement.^34,36,37

Behavioral health specialists. Psychotherapists, especially those trained in sex therapy, couples therapy, or cognitive behavioral therapy (CBT), are also typically on the treatment team. Multiple RCTs have found evidence of CBT’s effectiveness in the direct treatment of dyspareunia pain. Bergeron et al³⁵ found a 37.5% reduction in vulvar vestibulitis pain intensity during intercourse after patients completed group CBT. Another intent-to-treat RCT found that patients receiving CBT experienced more pain reduction (~ 30%) than patients who were treated with a topical steroid.³⁸

In addition to having a direct impact on pain, CBT has also been found to have a clinically and statistically significant positive impact on other aspects of sexual experience, such as overall sexuality, self-efficacy, overall sexual functioning, frequency of intercourse, and catastrophizing.^34,38 A recent meta-­analysis of RCTs found that about 80% of vaginismus patients were able to achieve penetrative intercourse after treatment with behavioral sex therapy or CBT.³⁹ This success rate was not exceeded by physical or surgical treatments.³⁹

When PTSD is thought to be a contributing factor, trauma therapy will likely be needed in addition to treatments for dyspareunia. First-line treatments for PTSD include cognitive processing therapy, prolonged exposure, trauma-focused CBT, and cognitive therapy.⁴⁰

Chronic pelvic pain with pain deep in the vagina or pelvis has been reduced by > 50%, compared with placebo, using medroxyprogesterone acetate.

Psychotherapists can also help patients reduce anxiety, reintroduce sexual contact without triggering pain or anxiety, address emotional and self-esteem effects of dyspareunia, address relationship issues, and refocus sexual encounters on pleasure rather than pain avoidance.^2-4 Despite patient reports of high treatment satisfaction following therapy,³⁸ many patients may initially lack confidence in psychotherapy as a treatment for pain³⁵ and may need to be educated on its effectiveness and multidimensional benefits.

Gynecologists. Often a gynecologist with specialization in pelvic pain is an essential member of the team for diagnostic clarification, recommendation of treatment options, and performance of more advanced treatments.^2,3 If pain has become chronic, the patient may also benefit from a pain management team and support groups.^2,3

Follow-up steps

Patients who screen negative for dyspareunia should be re-screened periodically. Continue to assess patients diagnosed with dyspareunia for vaginismus symptoms (if they are not initially present) to ensure that the treatment plan is appropriately adjusted. Once treatment has begun, ask about adverse effects and confidence in the treatment plan to minimize negative impacts on treatment adherence and to anticipate a need for a change in the treatment approach.^31,35 In addition to tracking treatment effects on pain, continue to assess for patient-centered outcomes such as emotional functioning, self-esteem, and sexual and relationship satisfaction.³⁴ The Female Sexual Function Index can be a useful tool to track symptoms.^27,34

Finally, patients who do not experience sufficient improvement in symptoms and functioning with initial treatment may need continued support and encouragement. Given the broad range of contributing factors and the high number of potential treatments, patients may find hope in learning that multiple other treatment options may be available.

CORRESPONDENCE
Adrienne A. Williams, PhD, Department of Family and Community Medicine, University of Illinois at Chicago College of Medicine, 1919 W Taylor Street, MC 663, Chicago, IL 60612; [email protected]

Dyspareunia is persistent or recurrent pain before, during, or after sexual contact and is not limited to cisgender individuals or vaginal intercourse.^1-3 With a prevalence as high as 45% in the United States,^2-5 it is one of the most common complaints in gynecologic practices.^5,6

Causes and contributing factors

There are many possible causes of dyspareunia.^2,4,6 While some patients have a single cause, most cases are complex, with multiple overlapping causes and maintaining factors.^4,6 Identifying each contributing factor can help you appropriately address all components.

Physical conditions. The range of physical contributors to dyspareunia includes inflammatory processes, structural abnormalities, musculoskeletal dysfunctions, pelvic organ disorders, injuries, iatrogenic effects, infections, allergic reactions, sensitization, hormonal changes, medication effects, adhesions, autoimmune disorders, and other pain syndromes (TABLE 1^2-4,6-11).

Inadequate arousal. One of the primary causes of pain during vaginal penetration is inadequate arousal and lubrication.^1,2,9-11 Arousal is the phase of the sexual response cycle that leads to genital tumescence and prepares the genitals for sexual contact through penile/clitoral erection, vaginal engorgement, and lubrication, which prevents pain and enhances pleasurable sensation.^9-11

While some physical conditions can lead to an inability to lubricate, the most common causes of inadequate lubrication are psychosocial-behavioral, wherein patients have the same physical ability to lubricate as patients without genital pain but do not progress through the arousal phase.^9-11 Behavioral factors such as inadequate or ineffective foreplay can fail to produce engorgement and lubrication, while psychosocial factors such as low attraction to partner, relationship stressors, anxiety, or low self-esteem can have an inhibitory effect on sexual arousal.^1,2,9-11 Psychosocial and behavioral factors may also be maintaining factors or consequences of dyspareunia, and need to be assessed and treated.^1,2,9-11

Psychological trauma. Exposure to psychological traumas and the development of posttraumatic stress disorder (PTSD) have been linked with the development of pain disorders in general and dyspareunia specifically. Most patients seeking treatment for chronic pain disorders have a history of physical or sexual abuse.¹² Changes in physiologic processes (eg, neurochemical, endocrine) that occur with PTSD interfere with the sexual response cycle, and sexual traumas specifically have been linked with pelvic floor dysfunction.^13,14 Additionally, when PTSD is caused by a sexual trauma, even consensual sexual encounters can trigger flashbacks, intrusive memories, hyperarousal, and muscle tension that interfere with the sexual response cycle and contribute to genital pain.¹³

Vaginismus is both a physiologic and psychological contributor to dyspareunia.^1,2,4 Patients experiencing pain can develop anxiety about repeated pain and involuntarily contract their pelvic muscles, thereby creating more pain, increasing anxiety, decreasing lubrication, and causing pelvic floor dysfunction.^1-4,6 Consequently, all patients with dyspareunia should be assessed and continually monitored for symptoms of vaginismus.

Continue to: Anxiety

Anxiety. As with other pain disorders, anxiety develops around pain triggers.^10,15 When expecting sexual activity, patients can experience extreme worry and panic attacks.^10,15,16 The distress of sexual encounters can interfere with physiologic arousal and sexual desire, impacting all phases of the sexual response cycle.^1,2

Relationship issues. Difficulty engaging in or avoidance of sexual activity can interfere with romantic relationships.^2,10,16 Severe pain or vaginismus contractions can prevent penetration, leading to unconsummated marriages and an inability to conceive through intercourse.¹⁰ The distress surrounding sexual encounters can precipitate erectile dysfunction in male partners, or partners may continue to demand sexual encounters despite the patient’s pain, further impacting the relationship and heightening sexual distress.¹⁰ These stressors have led to relationships ending, patients reluctantly agreeing to nonmonogamy to appease their partners, and patients avoiding relationships altogether.^10,16

Devalued self-image. Difficulties with sexuality and relationships impact the self-image of patients with dyspareunia. Diminished self-image may include feeling “inadequate” as a woman and as a sexual partner, or feeling like a “failure.”¹⁶ Women with dyspareunia often have more distress related to their body image, physical appearance, and genital self-image than do women without genital pain.¹⁷ Feeling resentment toward their body, or feeling “ugly,” embarrassed, shamed, “broken,” and “useless” also contribute to increased depressive symptoms found in patients with dyspareunia.^16,18

Making the diagnosis

Most patients do not report symptoms unless directly asked^2,7; therefore, it is recommended that all patients be screened as a part of an initial intake and before any genital exam (TABLE 2^{2-4,6,7,9,11,19,20}).^4,7,21 If this screen is positive, a separate appointment may be needed for a thorough evaluation and before any attempt is made at a genital exam.^4,7

Items to include in the clinical interview

Given the range of possible causes of dyspareunia and its contributing factors and symptoms, a thorough clinical interview is essential. Begin with a review of the patient’s complete medical and surgical history to identify possible known contributors to genital pain.⁴ Pregnancy history is of particular importance as the prevalence of postpartum dyspareunia is 35%, with risk being greater for patients who experienced dyspareunia symptoms before pregnancy.²²

Consider using a measure such as the Female Sexual Function Index or the McGill Pain Questionnaire to help patients more thoroughly describe their symptoms.

Knowing the location and quality of pain is important for differentiating between possible diagnoses, as is specifying dyspareunia as lifelong or acquired, superficial or deep, and primary or secondary.^1-4,6 Confirm the specific location(s) of pain—eg, at the introitus, in the vestibule, on the labia, in the perineum, or near the clitoris.^2,4,6 A diagram or model may be needed to help patients to localize pain.⁴

To help narrow the differential, include the following elements in your assessment: pain quality, timing (eg, initial onset, episode onset, episode duration, situational triggers), alleviating factors, symptoms in surrounding structures (eg, bladder, bowel, muscles, bones), sexual history, other areas of sexual functioning, history of psychological trauma, relationship effects, and mental health (TABLE 2^{2-4,6,7,9,11,19,20} and Table 3^23-28). Screening for a history of sexual trauma is particularly important, as a recent systematic review and meta-analysis found that women with a history of sexual assault had a 42% higher risk of gynecologic problems overall, a 74% higher risk of dyspareunia, and a 71% higher risk of vaginismus than women without a history of sexual assault.²⁹ Using measures such as the Female Sexual Function Index or the McGill Pain Questionnaire can help patients more thoroughly describe their symptoms (TABLE 3^23-28).³

Continue to: Guidelines for the physical exam

Before the exam, ensure the patient has not used any topical genital treatment in the past 2 weeks that may interfere with sensitivity to the exam.⁴ To decrease patients’ anxiety about the exam, remind them that they can stop the exam at any time.⁷ Also consider offering the use of a mirror to better pinpoint the location of pain, and to possibly help the patient learn more about her anatomy.^2,7

Begin the exam by palpating surrounding areas that may be involved in pain, including the abdomen and musculoskeletal features.^3,6,19 Next visually inspect the external genitalia for lesions, abrasions, discoloration, erythema, or other abnormal findings.^2,3,6 Ask the patient for permission before contacting the genitals. Because the labia may be a site of pain, apply gentle pressure in retracting it to fully examine the vestibule.^6,7 Contraction of the pelvic floor muscles during approach or initial palpation could signal possible vaginismus.⁴

After visual inspection of external genitalia, use a cotton swab to map the vulva and vestibule in a clockwise fashion to precisely identify any painful locations.^2-4,6 If the patient’s history of pain has been intermittent, it’s possible that the cotton swab will not elicit pain on the day of the initial exam, but it may on other days.⁴

Begin the internal exam by inserting a single finger into the first inch of the vagina and have the patient squeeze and release to assess tenderness, muscle tightness, and control.^2,6 Advance the finger further into the vagina and palpate clockwise, examining the levator muscles, obturator muscles, rectum, urethra, and bladder for abnormal tightness or reproduction of pain.^2,4,6 Complete a bimanual exam to evaluate the pelvic organs and adnexa.^2,4 If indicated, a more thorough evaluation of pelvic floor musculature can be performed by a physical therapist or gynecologist who specializes in pelvic pain.^2-4

If the patient consents to further evaluation, consider using a small speculum, advanced slowly, for further internal examination, noting any lesions, abrasions, discharge, ectropion, or tenderness.^2-4,7 A rectal exam may also be needed in cases of deep dyspareunia.⁶ Initial work-up may include a potassium hydroxide wet prep, sexually transmitted infection testing, and pelvic ultrasound.^2,4 In some cases, laparoscopy or biopsy may be needed.^2,4

Treatments for common causes

Treatment often begins with education about anatomy, to help patients communicate about symptoms and engage more fully in their care.³ Additional education may be needed on genital functioning and the necessity of adequate stimulation and lubrication prior to penetration.^1,2,9-11 A discussion of treatments for the wide range of possible causes of dyspareunia is outside the scope of this article. However, some basic behavioral changes may help patients address some of the more common contributing factors.

A recent systematic review and meta-analysis found that women with a history of sexual assault had a 74% higher risk of dyspareunia than women without such a history.

For example, if vaginal infection is suspected, advise patients to discontinue the use of harsh soaps, known vaginal irritants (eg, perfumed products, bath additives), and douches.³ Recommend using only ­preservative- and alcohol-free lubricants for sexual contact, and avoiding lubricants with added functions (eg, warming).³ It’s worth noting that avoidance of tight clothing and thong underwear due to possible risk for infections may not be necessary. A recent study found that women who frequently wore thong underwear (more than half of the time) were no more likely to develop urinary tract infections, yeast vaginitis, or bacterial vaginosis than those who avoid such items.³⁰ However, noncotton underwear fabric, rather than tightness, was associated with yeast vaginitis³⁰; therefore, patients may want to consider using only breathable underwear.³

Continue to: Medication

Medication. Medication may be used to treat the underlying contributing conditions or the symptom of pain directly. Some common options are particularly important for patients whose dyspareunia does not have an identifiable cause. These medications include anti-inflammatory agents, topical anesthetics, tricyclic antidepressants, and hormonal treatments.^2-4 Since effectiveness varies based on subtypes of pain, select a medication according to the location, timing, and hypothesized mechanism of pain.^3,31,32

Medication for deep pain. A meta-analysis and systematic review found that patients with some types of chronic pelvic pain with pain deep in the vagina or pelvis experienced greater than 50% reduction in pain using medroxyprogesterone acetate compared with placebo.³³ Other treatments for deep pain depend on physical exam findings.

Medication for superficial pain. Many remedies have been tried, with at least 26 different treatments for vulvodynia pain alone.¹⁶ Only some of these treatments have supporting evidence. For patients with vulvar pain, an intent-to-treat RCT found that patients using a topical steroid experienced a 23% reduction in pain from pre-treatment to 6-month follow-up.³²

Surgery is also effective for vulvar pain.^34,35 For provoked vestibulodynia (in which pain is localized to the vestibule and triggered by contact with the vulva), or vulvar vestibulitis, RCTs have found that vestibulectomy has stronger effects on pain than other treatments,^31,35 with a 53% reduction in pain during intercourse and a 70% reduction in vestibular pain overall.³⁵ However, while vestibulectomy is effective for provoked vestibulodynia, it is not recommended for generalized vulvodynia, in which pain is diffuse across the vulva and occurs without vulvar contact.³⁴

Unsupported treatments. A number of other treatments have not yet been found effective. Although lidocaine for vulvar pain is often used, RCTs have not found any significant reduction in symptoms, and a ­double-blind RCT found that lidocaine ointment actually performed worse than placebo.^31,34 Similarly, oral tricyclics have not been found to decrease vulvar pain more than placebo in double-blind studies.^31,34 Furthermore, a meta-analysis of RCTs comparing treatments with placebo for vestibular pain found no significant decrease in dyspareunia for topical conjugated estrogen, topical lidocaine, oral desipramine, oral desipramine with topical lidocaine, laser therapy, or transcranial direct current.³²

Tx risks to consider. Risks and benefits of dyspareunia treatment options should be thoroughly weighed and discussed with the patient.^2-4 Vestibulectomy, despite reducing pain for many patients, has led to increased pain for 9% of patients who underwent the procedure.³⁵ Topical treatments may lead to allergic reactions, inflammation, and worsening of symptoms,⁴ and hormonal treatments have been found to increase the risk of weight gain and bloating and are not appropriate for patients trying to conceive.³³

Coordinate care with other providers

While medications and surgery can reduce pain, they have not been shown to improve other aspects of sexual functioning such as sexual satisfaction, frequency of sexual intercourse, or overall sense of sexual functioning.³⁵ Additionally, pain reduction does not address muscle tension, anxiety, self-­esteem, and relationship problems. As a result, a multidisciplinary approach is generally needed.^3,4,32,33

Continue to: Physical therapists

Physical therapists. Pelvic floor physical therapists are often members of the dyspareunia treatment team and can provide a thorough evaluation and treatment of pelvic floor disorders.^2-4 An RCT with intent-to-treat analysis found that pain was reduced by 71% following pelvic floor physical therapy.³⁶ Another RCT found that 90% of patients reported a clinically meaningful decrease in pain with pelvic floor physical therapy.³⁷ In addition to addressing pain, pelvic floor physical therapy has also been found to improve sexual functioning, sexual satisfaction, distress, and patient perception of improvement.^34,36,37

Behavioral health specialists. Psychotherapists, especially those trained in sex therapy, couples therapy, or cognitive behavioral therapy (CBT), are also typically on the treatment team. Multiple RCTs have found evidence of CBT’s effectiveness in the direct treatment of dyspareunia pain. Bergeron et al³⁵ found a 37.5% reduction in vulvar vestibulitis pain intensity during intercourse after patients completed group CBT. Another intent-to-treat RCT found that patients receiving CBT experienced more pain reduction (~ 30%) than patients who were treated with a topical steroid.³⁸

In addition to having a direct impact on pain, CBT has also been found to have a clinically and statistically significant positive impact on other aspects of sexual experience, such as overall sexuality, self-efficacy, overall sexual functioning, frequency of intercourse, and catastrophizing.^34,38 A recent meta-­analysis of RCTs found that about 80% of vaginismus patients were able to achieve penetrative intercourse after treatment with behavioral sex therapy or CBT.³⁹ This success rate was not exceeded by physical or surgical treatments.³⁹

When PTSD is thought to be a contributing factor, trauma therapy will likely be needed in addition to treatments for dyspareunia. First-line treatments for PTSD include cognitive processing therapy, prolonged exposure, trauma-focused CBT, and cognitive therapy.⁴⁰

Chronic pelvic pain with pain deep in the vagina or pelvis has been reduced by > 50%, compared with placebo, using medroxyprogesterone acetate.

Psychotherapists can also help patients reduce anxiety, reintroduce sexual contact without triggering pain or anxiety, address emotional and self-esteem effects of dyspareunia, address relationship issues, and refocus sexual encounters on pleasure rather than pain avoidance.^2-4 Despite patient reports of high treatment satisfaction following therapy,³⁸ many patients may initially lack confidence in psychotherapy as a treatment for pain³⁵ and may need to be educated on its effectiveness and multidimensional benefits.

Gynecologists. Often a gynecologist with specialization in pelvic pain is an essential member of the team for diagnostic clarification, recommendation of treatment options, and performance of more advanced treatments.^2,3 If pain has become chronic, the patient may also benefit from a pain management team and support groups.^2,3

Follow-up steps

Patients who screen negative for dyspareunia should be re-screened periodically. Continue to assess patients diagnosed with dyspareunia for vaginismus symptoms (if they are not initially present) to ensure that the treatment plan is appropriately adjusted. Once treatment has begun, ask about adverse effects and confidence in the treatment plan to minimize negative impacts on treatment adherence and to anticipate a need for a change in the treatment approach.^31,35 In addition to tracking treatment effects on pain, continue to assess for patient-centered outcomes such as emotional functioning, self-esteem, and sexual and relationship satisfaction.³⁴ The Female Sexual Function Index can be a useful tool to track symptoms.^27,34

Finally, patients who do not experience sufficient improvement in symptoms and functioning with initial treatment may need continued support and encouragement. Given the broad range of contributing factors and the high number of potential treatments, patients may find hope in learning that multiple other treatment options may be available.

CORRESPONDENCE
Adrienne A. Williams, PhD, Department of Family and Community Medicine, University of Illinois at Chicago College of Medicine, 1919 W Taylor Street, MC 663, Chicago, IL 60612; [email protected]

Dyspareunia is persistent or recurrent pain before, during, or after sexual contact and is not limited to cisgender individuals or vaginal intercourse.^1-3 With a prevalence as high as 45% in the United States,^2-5 it is one of the most common complaints in gynecologic practices.^5,6

Causes and contributing factors

There are many possible causes of dyspareunia.^2,4,6 While some patients have a single cause, most cases are complex, with multiple overlapping causes and maintaining factors.^4,6 Identifying each contributing factor can help you appropriately address all components.

Physical conditions. The range of physical contributors to dyspareunia includes inflammatory processes, structural abnormalities, musculoskeletal dysfunctions, pelvic organ disorders, injuries, iatrogenic effects, infections, allergic reactions, sensitization, hormonal changes, medication effects, adhesions, autoimmune disorders, and other pain syndromes (TABLE 1^2-4,6-11).

Inadequate arousal. One of the primary causes of pain during vaginal penetration is inadequate arousal and lubrication.^1,2,9-11 Arousal is the phase of the sexual response cycle that leads to genital tumescence and prepares the genitals for sexual contact through penile/clitoral erection, vaginal engorgement, and lubrication, which prevents pain and enhances pleasurable sensation.^9-11

While some physical conditions can lead to an inability to lubricate, the most common causes of inadequate lubrication are psychosocial-behavioral, wherein patients have the same physical ability to lubricate as patients without genital pain but do not progress through the arousal phase.^9-11 Behavioral factors such as inadequate or ineffective foreplay can fail to produce engorgement and lubrication, while psychosocial factors such as low attraction to partner, relationship stressors, anxiety, or low self-esteem can have an inhibitory effect on sexual arousal.^1,2,9-11 Psychosocial and behavioral factors may also be maintaining factors or consequences of dyspareunia, and need to be assessed and treated.^1,2,9-11

Psychological trauma. Exposure to psychological traumas and the development of posttraumatic stress disorder (PTSD) have been linked with the development of pain disorders in general and dyspareunia specifically. Most patients seeking treatment for chronic pain disorders have a history of physical or sexual abuse.¹² Changes in physiologic processes (eg, neurochemical, endocrine) that occur with PTSD interfere with the sexual response cycle, and sexual traumas specifically have been linked with pelvic floor dysfunction.^13,14 Additionally, when PTSD is caused by a sexual trauma, even consensual sexual encounters can trigger flashbacks, intrusive memories, hyperarousal, and muscle tension that interfere with the sexual response cycle and contribute to genital pain.¹³

Vaginismus is both a physiologic and psychological contributor to dyspareunia.^1,2,4 Patients experiencing pain can develop anxiety about repeated pain and involuntarily contract their pelvic muscles, thereby creating more pain, increasing anxiety, decreasing lubrication, and causing pelvic floor dysfunction.^1-4,6 Consequently, all patients with dyspareunia should be assessed and continually monitored for symptoms of vaginismus.

Continue to: Anxiety

Anxiety. As with other pain disorders, anxiety develops around pain triggers.^10,15 When expecting sexual activity, patients can experience extreme worry and panic attacks.^10,15,16 The distress of sexual encounters can interfere with physiologic arousal and sexual desire, impacting all phases of the sexual response cycle.^1,2

Relationship issues. Difficulty engaging in or avoidance of sexual activity can interfere with romantic relationships.^2,10,16 Severe pain or vaginismus contractions can prevent penetration, leading to unconsummated marriages and an inability to conceive through intercourse.¹⁰ The distress surrounding sexual encounters can precipitate erectile dysfunction in male partners, or partners may continue to demand sexual encounters despite the patient’s pain, further impacting the relationship and heightening sexual distress.¹⁰ These stressors have led to relationships ending, patients reluctantly agreeing to nonmonogamy to appease their partners, and patients avoiding relationships altogether.^10,16

Devalued self-image. Difficulties with sexuality and relationships impact the self-image of patients with dyspareunia. Diminished self-image may include feeling “inadequate” as a woman and as a sexual partner, or feeling like a “failure.”¹⁶ Women with dyspareunia often have more distress related to their body image, physical appearance, and genital self-image than do women without genital pain.¹⁷ Feeling resentment toward their body, or feeling “ugly,” embarrassed, shamed, “broken,” and “useless” also contribute to increased depressive symptoms found in patients with dyspareunia.^16,18

Making the diagnosis

Most patients do not report symptoms unless directly asked^2,7; therefore, it is recommended that all patients be screened as a part of an initial intake and before any genital exam (TABLE 2^{2-4,6,7,9,11,19,20}).^4,7,21 If this screen is positive, a separate appointment may be needed for a thorough evaluation and before any attempt is made at a genital exam.^4,7

Items to include in the clinical interview

Given the range of possible causes of dyspareunia and its contributing factors and symptoms, a thorough clinical interview is essential. Begin with a review of the patient’s complete medical and surgical history to identify possible known contributors to genital pain.⁴ Pregnancy history is of particular importance as the prevalence of postpartum dyspareunia is 35%, with risk being greater for patients who experienced dyspareunia symptoms before pregnancy.²²

Consider using a measure such as the Female Sexual Function Index or the McGill Pain Questionnaire to help patients more thoroughly describe their symptoms.

Knowing the location and quality of pain is important for differentiating between possible diagnoses, as is specifying dyspareunia as lifelong or acquired, superficial or deep, and primary or secondary.^1-4,6 Confirm the specific location(s) of pain—eg, at the introitus, in the vestibule, on the labia, in the perineum, or near the clitoris.^2,4,6 A diagram or model may be needed to help patients to localize pain.⁴

To help narrow the differential, include the following elements in your assessment: pain quality, timing (eg, initial onset, episode onset, episode duration, situational triggers), alleviating factors, symptoms in surrounding structures (eg, bladder, bowel, muscles, bones), sexual history, other areas of sexual functioning, history of psychological trauma, relationship effects, and mental health (TABLE 2^{2-4,6,7,9,11,19,20} and Table 3^23-28). Screening for a history of sexual trauma is particularly important, as a recent systematic review and meta-analysis found that women with a history of sexual assault had a 42% higher risk of gynecologic problems overall, a 74% higher risk of dyspareunia, and a 71% higher risk of vaginismus than women without a history of sexual assault.²⁹ Using measures such as the Female Sexual Function Index or the McGill Pain Questionnaire can help patients more thoroughly describe their symptoms (TABLE 3^23-28).³

Continue to: Guidelines for the physical exam

Before the exam, ensure the patient has not used any topical genital treatment in the past 2 weeks that may interfere with sensitivity to the exam.⁴ To decrease patients’ anxiety about the exam, remind them that they can stop the exam at any time.⁷ Also consider offering the use of a mirror to better pinpoint the location of pain, and to possibly help the patient learn more about her anatomy.^2,7

Begin the exam by palpating surrounding areas that may be involved in pain, including the abdomen and musculoskeletal features.^3,6,19 Next visually inspect the external genitalia for lesions, abrasions, discoloration, erythema, or other abnormal findings.^2,3,6 Ask the patient for permission before contacting the genitals. Because the labia may be a site of pain, apply gentle pressure in retracting it to fully examine the vestibule.^6,7 Contraction of the pelvic floor muscles during approach or initial palpation could signal possible vaginismus.⁴

After visual inspection of external genitalia, use a cotton swab to map the vulva and vestibule in a clockwise fashion to precisely identify any painful locations.^2-4,6 If the patient’s history of pain has been intermittent, it’s possible that the cotton swab will not elicit pain on the day of the initial exam, but it may on other days.⁴

Begin the internal exam by inserting a single finger into the first inch of the vagina and have the patient squeeze and release to assess tenderness, muscle tightness, and control.^2,6 Advance the finger further into the vagina and palpate clockwise, examining the levator muscles, obturator muscles, rectum, urethra, and bladder for abnormal tightness or reproduction of pain.^2,4,6 Complete a bimanual exam to evaluate the pelvic organs and adnexa.^2,4 If indicated, a more thorough evaluation of pelvic floor musculature can be performed by a physical therapist or gynecologist who specializes in pelvic pain.^2-4

If the patient consents to further evaluation, consider using a small speculum, advanced slowly, for further internal examination, noting any lesions, abrasions, discharge, ectropion, or tenderness.^2-4,7 A rectal exam may also be needed in cases of deep dyspareunia.⁶ Initial work-up may include a potassium hydroxide wet prep, sexually transmitted infection testing, and pelvic ultrasound.^2,4 In some cases, laparoscopy or biopsy may be needed.^2,4

Treatments for common causes

Treatment often begins with education about anatomy, to help patients communicate about symptoms and engage more fully in their care.³ Additional education may be needed on genital functioning and the necessity of adequate stimulation and lubrication prior to penetration.^1,2,9-11 A discussion of treatments for the wide range of possible causes of dyspareunia is outside the scope of this article. However, some basic behavioral changes may help patients address some of the more common contributing factors.

A recent systematic review and meta-analysis found that women with a history of sexual assault had a 74% higher risk of dyspareunia than women without such a history.

For example, if vaginal infection is suspected, advise patients to discontinue the use of harsh soaps, known vaginal irritants (eg, perfumed products, bath additives), and douches.³ Recommend using only ­preservative- and alcohol-free lubricants for sexual contact, and avoiding lubricants with added functions (eg, warming).³ It’s worth noting that avoidance of tight clothing and thong underwear due to possible risk for infections may not be necessary. A recent study found that women who frequently wore thong underwear (more than half of the time) were no more likely to develop urinary tract infections, yeast vaginitis, or bacterial vaginosis than those who avoid such items.³⁰ However, noncotton underwear fabric, rather than tightness, was associated with yeast vaginitis³⁰; therefore, patients may want to consider using only breathable underwear.³

Continue to: Medication

Medication. Medication may be used to treat the underlying contributing conditions or the symptom of pain directly. Some common options are particularly important for patients whose dyspareunia does not have an identifiable cause. These medications include anti-inflammatory agents, topical anesthetics, tricyclic antidepressants, and hormonal treatments.^2-4 Since effectiveness varies based on subtypes of pain, select a medication according to the location, timing, and hypothesized mechanism of pain.^3,31,32

Medication for deep pain. A meta-analysis and systematic review found that patients with some types of chronic pelvic pain with pain deep in the vagina or pelvis experienced greater than 50% reduction in pain using medroxyprogesterone acetate compared with placebo.³³ Other treatments for deep pain depend on physical exam findings.

Medication for superficial pain. Many remedies have been tried, with at least 26 different treatments for vulvodynia pain alone.¹⁶ Only some of these treatments have supporting evidence. For patients with vulvar pain, an intent-to-treat RCT found that patients using a topical steroid experienced a 23% reduction in pain from pre-treatment to 6-month follow-up.³²

Surgery is also effective for vulvar pain.^34,35 For provoked vestibulodynia (in which pain is localized to the vestibule and triggered by contact with the vulva), or vulvar vestibulitis, RCTs have found that vestibulectomy has stronger effects on pain than other treatments,^31,35 with a 53% reduction in pain during intercourse and a 70% reduction in vestibular pain overall.³⁵ However, while vestibulectomy is effective for provoked vestibulodynia, it is not recommended for generalized vulvodynia, in which pain is diffuse across the vulva and occurs without vulvar contact.³⁴

Unsupported treatments. A number of other treatments have not yet been found effective. Although lidocaine for vulvar pain is often used, RCTs have not found any significant reduction in symptoms, and a ­double-blind RCT found that lidocaine ointment actually performed worse than placebo.^31,34 Similarly, oral tricyclics have not been found to decrease vulvar pain more than placebo in double-blind studies.^31,34 Furthermore, a meta-analysis of RCTs comparing treatments with placebo for vestibular pain found no significant decrease in dyspareunia for topical conjugated estrogen, topical lidocaine, oral desipramine, oral desipramine with topical lidocaine, laser therapy, or transcranial direct current.³²

Tx risks to consider. Risks and benefits of dyspareunia treatment options should be thoroughly weighed and discussed with the patient.^2-4 Vestibulectomy, despite reducing pain for many patients, has led to increased pain for 9% of patients who underwent the procedure.³⁵ Topical treatments may lead to allergic reactions, inflammation, and worsening of symptoms,⁴ and hormonal treatments have been found to increase the risk of weight gain and bloating and are not appropriate for patients trying to conceive.³³

Coordinate care with other providers

While medications and surgery can reduce pain, they have not been shown to improve other aspects of sexual functioning such as sexual satisfaction, frequency of sexual intercourse, or overall sense of sexual functioning.³⁵ Additionally, pain reduction does not address muscle tension, anxiety, self-­esteem, and relationship problems. As a result, a multidisciplinary approach is generally needed.^3,4,32,33

Continue to: Physical therapists

Physical therapists. Pelvic floor physical therapists are often members of the dyspareunia treatment team and can provide a thorough evaluation and treatment of pelvic floor disorders.^2-4 An RCT with intent-to-treat analysis found that pain was reduced by 71% following pelvic floor physical therapy.³⁶ Another RCT found that 90% of patients reported a clinically meaningful decrease in pain with pelvic floor physical therapy.³⁷ In addition to addressing pain, pelvic floor physical therapy has also been found to improve sexual functioning, sexual satisfaction, distress, and patient perception of improvement.^34,36,37

Behavioral health specialists. Psychotherapists, especially those trained in sex therapy, couples therapy, or cognitive behavioral therapy (CBT), are also typically on the treatment team. Multiple RCTs have found evidence of CBT’s effectiveness in the direct treatment of dyspareunia pain. Bergeron et al³⁵ found a 37.5% reduction in vulvar vestibulitis pain intensity during intercourse after patients completed group CBT. Another intent-to-treat RCT found that patients receiving CBT experienced more pain reduction (~ 30%) than patients who were treated with a topical steroid.³⁸

In addition to having a direct impact on pain, CBT has also been found to have a clinically and statistically significant positive impact on other aspects of sexual experience, such as overall sexuality, self-efficacy, overall sexual functioning, frequency of intercourse, and catastrophizing.^34,38 A recent meta-­analysis of RCTs found that about 80% of vaginismus patients were able to achieve penetrative intercourse after treatment with behavioral sex therapy or CBT.³⁹ This success rate was not exceeded by physical or surgical treatments.³⁹

When PTSD is thought to be a contributing factor, trauma therapy will likely be needed in addition to treatments for dyspareunia. First-line treatments for PTSD include cognitive processing therapy, prolonged exposure, trauma-focused CBT, and cognitive therapy.⁴⁰

Chronic pelvic pain with pain deep in the vagina or pelvis has been reduced by > 50%, compared with placebo, using medroxyprogesterone acetate.

Psychotherapists can also help patients reduce anxiety, reintroduce sexual contact without triggering pain or anxiety, address emotional and self-esteem effects of dyspareunia, address relationship issues, and refocus sexual encounters on pleasure rather than pain avoidance.^2-4 Despite patient reports of high treatment satisfaction following therapy,³⁸ many patients may initially lack confidence in psychotherapy as a treatment for pain³⁵ and may need to be educated on its effectiveness and multidimensional benefits.

Gynecologists. Often a gynecologist with specialization in pelvic pain is an essential member of the team for diagnostic clarification, recommendation of treatment options, and performance of more advanced treatments.^2,3 If pain has become chronic, the patient may also benefit from a pain management team and support groups.^2,3

Follow-up steps

Patients who screen negative for dyspareunia should be re-screened periodically. Continue to assess patients diagnosed with dyspareunia for vaginismus symptoms (if they are not initially present) to ensure that the treatment plan is appropriately adjusted. Once treatment has begun, ask about adverse effects and confidence in the treatment plan to minimize negative impacts on treatment adherence and to anticipate a need for a change in the treatment approach.^31,35 In addition to tracking treatment effects on pain, continue to assess for patient-centered outcomes such as emotional functioning, self-esteem, and sexual and relationship satisfaction.³⁴ The Female Sexual Function Index can be a useful tool to track symptoms.^27,34

Finally, patients who do not experience sufficient improvement in symptoms and functioning with initial treatment may need continued support and encouragement. Given the broad range of contributing factors and the high number of potential treatments, patients may find hope in learning that multiple other treatment options may be available.

CORRESPONDENCE
Adrienne A. Williams, PhD, Department of Family and Community Medicine, University of Illinois at Chicago College of Medicine, 1919 W Taylor Street, MC 663, Chicago, IL 60612; [email protected]

Atrial fibrillation (AF) is a common problem confronting family physicians. In this issue of JFP, we offer 2 articles about AF: one on prevention and one on treatment. Both provide evidence-based guidance to help you refine your care. But gaps remain. I’ll get to that in a bit.

Prevention. This month’s PURL¹ discusses a randomized controlled trial (RCT) that enrolled moderate alcohol drinkers with AF.² Compared to those who continued to drink moderately, those who reduced their alcohol consumption to 2 drinks per week had a significant reduction in recurrent AF (73% vs 53%), fewer hospitalizations (20% vs 9%), and less moderate or severe symptoms (32% vs 10%). Although previous studies of moderate alcohol consumption have shown positive effects on heart disease, this study and other more recent studies cast serious doubt on this assertion.³

The dilemma is that your patient with a wearable exercise monitoring device will know she has a potentially dangerous condition, but there is no evidence that treating it will result in more benefit than harm.

Treatment. In their applied evidence article, Osayande and Sharma⁴ pose the question: When is catheter ablation a sound option for your patient with AF? They give us an excellent, evidence-based answer and remind us that we must focus on the treatment goals: to prevent stroke and to control symptoms. They recommend a stepwise approach, starting with rate control, progressing to rhythm control, and saving catheter ablation for resistant cases. In nearly all cases, anticoagulation to prevent stroke must be a part of treatment, with the exception of those with very low risk (so-called “lone atrial fibrillation”).

Screening. And what about screening for asymptomatic AF? The US Preventive Services Task Force recently reaffirmed its conclusion that there is insufficient evidence for screening for asymptomatic AF (a topic discussed in an online Practice Alert Brief⁵).⁶ Since wearable exercise-monitoring devices can detect heart arrhythmias (and are advertised for this purpose), a patient may present after receiving a notification about asymptomatic AF. What shall we do in these cases? The dilemma is that your patient will know she has a potentially dangerous condition, but there is no evidence that treating it will result in more benefit than harm.

A recently published study suggests that we should be very cautious in recommending treatment. In an RCT of patients ages 70 to 90 years, 1501 patients received an implantable loop recorder, while 4503 received routine health care; median follow-up was 64.5 months.⁷ Although more cases of AF were detected (32% in the monitored group vs 12% in the usual care group), and oral anticoagulation treatment was started more frequently (30% vs 13%, respectively), there was no significant difference in the proportion of patients who had a stroke or systemic arterial embolism (4.5% vs 5.6%).⁷ Until we have more data, reassurance seems to be the best recommendation for asymptomatic AF.

Atrial fibrillation (AF) is a common problem confronting family physicians. In this issue of JFP, we offer 2 articles about AF: one on prevention and one on treatment. Both provide evidence-based guidance to help you refine your care. But gaps remain. I’ll get to that in a bit.

Prevention. This month’s PURL¹ discusses a randomized controlled trial (RCT) that enrolled moderate alcohol drinkers with AF.² Compared to those who continued to drink moderately, those who reduced their alcohol consumption to 2 drinks per week had a significant reduction in recurrent AF (73% vs 53%), fewer hospitalizations (20% vs 9%), and less moderate or severe symptoms (32% vs 10%). Although previous studies of moderate alcohol consumption have shown positive effects on heart disease, this study and other more recent studies cast serious doubt on this assertion.³

The dilemma is that your patient with a wearable exercise monitoring device will know she has a potentially dangerous condition, but there is no evidence that treating it will result in more benefit than harm.

Treatment. In their applied evidence article, Osayande and Sharma⁴ pose the question: When is catheter ablation a sound option for your patient with AF? They give us an excellent, evidence-based answer and remind us that we must focus on the treatment goals: to prevent stroke and to control symptoms. They recommend a stepwise approach, starting with rate control, progressing to rhythm control, and saving catheter ablation for resistant cases. In nearly all cases, anticoagulation to prevent stroke must be a part of treatment, with the exception of those with very low risk (so-called “lone atrial fibrillation”).

Screening. And what about screening for asymptomatic AF? The US Preventive Services Task Force recently reaffirmed its conclusion that there is insufficient evidence for screening for asymptomatic AF (a topic discussed in an online Practice Alert Brief⁵).⁶ Since wearable exercise-monitoring devices can detect heart arrhythmias (and are advertised for this purpose), a patient may present after receiving a notification about asymptomatic AF. What shall we do in these cases? The dilemma is that your patient will know she has a potentially dangerous condition, but there is no evidence that treating it will result in more benefit than harm.

A recently published study suggests that we should be very cautious in recommending treatment. In an RCT of patients ages 70 to 90 years, 1501 patients received an implantable loop recorder, while 4503 received routine health care; median follow-up was 64.5 months.⁷ Although more cases of AF were detected (32% in the monitored group vs 12% in the usual care group), and oral anticoagulation treatment was started more frequently (30% vs 13%, respectively), there was no significant difference in the proportion of patients who had a stroke or systemic arterial embolism (4.5% vs 5.6%).⁷ Until we have more data, reassurance seems to be the best recommendation for asymptomatic AF.

Atrial fibrillation (AF) is a common problem confronting family physicians. In this issue of JFP, we offer 2 articles about AF: one on prevention and one on treatment. Both provide evidence-based guidance to help you refine your care. But gaps remain. I’ll get to that in a bit.

Prevention. This month’s PURL¹ discusses a randomized controlled trial (RCT) that enrolled moderate alcohol drinkers with AF.² Compared to those who continued to drink moderately, those who reduced their alcohol consumption to 2 drinks per week had a significant reduction in recurrent AF (73% vs 53%), fewer hospitalizations (20% vs 9%), and less moderate or severe symptoms (32% vs 10%). Although previous studies of moderate alcohol consumption have shown positive effects on heart disease, this study and other more recent studies cast serious doubt on this assertion.³

The dilemma is that your patient with a wearable exercise monitoring device will know she has a potentially dangerous condition, but there is no evidence that treating it will result in more benefit than harm.

Treatment. In their applied evidence article, Osayande and Sharma⁴ pose the question: When is catheter ablation a sound option for your patient with AF? They give us an excellent, evidence-based answer and remind us that we must focus on the treatment goals: to prevent stroke and to control symptoms. They recommend a stepwise approach, starting with rate control, progressing to rhythm control, and saving catheter ablation for resistant cases. In nearly all cases, anticoagulation to prevent stroke must be a part of treatment, with the exception of those with very low risk (so-called “lone atrial fibrillation”).

Screening. And what about screening for asymptomatic AF? The US Preventive Services Task Force recently reaffirmed its conclusion that there is insufficient evidence for screening for asymptomatic AF (a topic discussed in an online Practice Alert Brief⁵).⁶ Since wearable exercise-monitoring devices can detect heart arrhythmias (and are advertised for this purpose), a patient may present after receiving a notification about asymptomatic AF. What shall we do in these cases? The dilemma is that your patient will know she has a potentially dangerous condition, but there is no evidence that treating it will result in more benefit than harm.

A recently published study suggests that we should be very cautious in recommending treatment. In an RCT of patients ages 70 to 90 years, 1501 patients received an implantable loop recorder, while 4503 received routine health care; median follow-up was 64.5 months.⁷ Although more cases of AF were detected (32% in the monitored group vs 12% in the usual care group), and oral anticoagulation treatment was started more frequently (30% vs 13%, respectively), there was no significant difference in the proportion of patients who had a stroke or systemic arterial embolism (4.5% vs 5.6%).⁷ Until we have more data, reassurance seems to be the best recommendation for asymptomatic AF.

In a typical year, the Advisory Committee on Immunization Practices (ACIP) has three 1.5- to 2-day meetings to make recommendations for the use of new and existing vaccines in the US population. However, 2021 was not a typical year. Last year, ACIP held 17 meetings for a total of 127 hours. Most of these were related to vaccines to prevent COVID-19. There are now 3 COVID-19 vaccines authorized for use in the United States: the 2-dose mRNA-based Pfizer-BioNTech/Comirnaty and Moderna COVID-19 vaccines and the single-dose adenovirus, vector-based Janssen (Johnson & Johnson) COVID-19 vaccine.

TABLE 1¹ includes the actions taken by the ACIP from late 2020 through 2021 related to COVID-19 vaccines. All of these recommendations except 1 occurred after the US Food and Drug Administration (FDA) approved the product using an emergency use authorization (EUA). The exception is the recommendation for use of the Pfizer-BioNTech COVID-19 vaccine (BNT162b2) for those ages 16 years and older, which was approved under the normal process 8 months after widespread use under an EUA.

Hepatitis B vaccine now for all nonimmune adults up through 59 years

Since the introduction of hepatitis B (HepB) vaccines in 1980, the incidence of hepatitis B virus (HBV) infections in the United States has been reduced dramatically; there were an estimated 287,000 cases in 1985² and 19,200 in 2014.³ However, the incidence among adults has not declined in recent years and among someage groups has actually increased. Among those ages 40 to 49 years, the rate went from 1.9 per 100,000 in 2011⁴ to 2.7 per 100,000 population in 2019.⁵ In those ages 50 to 59, there was an increase from 1.1 to 1.6 per 100,000 population over the same period of time.^4,5

Recommendations for using HepB vaccine in adults have been based on risk that involves individual behavior, occupation, and medical conditions (TABLE 2⁶). The presence of these risk factors is often unknown to medical professionals, who rarely ask about or document them. And patients can be reluctant to disclose them for fear of being stigmatized. The consequence has been a low rate of vaccination in at-risk adults.

At its November 2021 meeting, ACIP accepted the advice of the Hepatitis Work Group to move to a universal adult recommendation through age 59.⁷ ACIP believed that the incidence of acute infection in those ages 60 and older was too low to merit a universal recommendation. The new recommendation states that all adults through age 59 years who are not immune to HBV through vaccination or prior infection should receive a HepB vaccine series, as should those 60 years and older with a risk factor (TABLE 2⁶). If a patient’s immune status is unknown, ACIP recommends administering the vaccine, as there are no documented harmful effects of doing so in an individual with immunity.

Multiple HepB vaccine products are available for adults. Two are recombinant-based and require 3 doses: Engerix-B (GlaxoSmithKline) and Recombivax HB (Merck). One is recombinant based and requires only 2 doses: Heplisav-B (Dynavax Technologies). A new product recently approved by the FDA, ­PREHEVBRIO (VBI Vaccines), is another recombinant 3-dose option that the ACIP will consider early in 2022. HepB and HepA vaccines can also be co-administered with Twinrix (GlaxoSmithKline).

Pneumococcal vaccines: New PCV vaccines alter prescribing choices

The ACIP recommendations for pneumococcal vaccines in adults have been very confusing, involving 2 vaccines: PCV13 (Prevnar13, Pfizer) and PPSV23 (Pneumovax23, Merck). Both PCV13 and PPSV23 given in series were recommended for immunocompromised patients, but only PPSV23 was recommended for those with chronic medical conditions. For those 65 and older, PPSV23 was recommended for all individuals (including those with no chronic or immunocompromising condition), and PCV13 was recommended for those with immunocompromising conditions. Other adults in this older age group could receive PCV13 based on individual risk and shared clinical decision making.⁸

Continue to: This past year...

This past year, 2 new PCV vaccines were approved by the FDA: PCV15 (Vaxneuvance, Merck) and PCV20 (Prevnar20, Pfizer). While considering these new vaccines, the ACIP re-­assessed its entire approval of pneumococcal vaccines. First, they retained the cutoff for universal pneumococcal vaccination at 65 years. For those younger than 65, they combined chronic medical conditions and immunocompromising conditions into a single at-risk group (TABLE 3⁹). They then issued the same recommendation for older adults and those younger than 65 with risks: to receive a PCV vaccine, either PCV15 or PCV20. If they receive PCV15, it should be followed by PPSV23. PPSV23 is not recommended for those who receive PCV20. Therefore, PPSV23 is no longer routinely recommended for adults unless PCV15 is the PCV of choice.⁹ Clinical guidance on the use of PCV vaccines will be published in early 2022.

Zoster vaccine for younger adults

Recombinant zoster vaccine (RZV) has been licensed and recommended in the United States since 2017 in a 2-dose schedule for adults ages 50 years and older. In the summer of 2021, the FDA expanded the indication for use of RZV to include individuals 18 to 49 years of age who are or will be immunodeficient or immunosuppressed due to known disease or therapy. In October, the ACIP agreed and recommended 2 RZV doses for those 19 years and older in these risk groups (TABLE 4¹⁰).

This recommendation was based on the elevated risk of herpes zoster documented in those with immune-suppressing conditions and therapies. In the conditions studied, the incidence in these younger adults exceeded that for older adults, for whom the vaccine is recommended.¹⁰ There are many immune conditions and immune-suppressing medications. The ACIP Zoster Work Group did not have efficacy and safety information on the use of RZV in each one of them, even though their recommendation includes them all. Many of these patients are under the care of specialists whose specialty societies had been recommending zoster vaccine for their patients, off label, prior to the FDA authorization.

Rabies vaccine is now available in 2-dose schedule

People who should receive rabies pre-exposure prophylaxis (PrEP) with rabies vaccine include laboratory personnel who work with rabies virus, biologists who work with bats, animal care professionals, wildlife biologists, veterinarians, and travelers who may be at risk of encountering rabid dogs. The recommendation has been for 3 doses of rabies vaccine at 0, 7, and 21-28 days. The ACIP voted at its June 2021 meeting to adopt a 2-dose PrEP schedule of 0 and 7 days.¹¹ This will be especially helpful to travelers who want to complete the recommended doses prior to departure. Those who have sustained risk over time can elect to have a third dose after 21 days and before 3 years, or elect to have titers checked. More detailed clinical advice will be published in the CDC’s Morbidity and Mortality Weekly Report in 2022.

Dengue vaccine: New rec for those 9-16 years

In 2019, the FDA approved the first dengue vaccine for use in the United States for children 9 to 16 years old who had laboratory-­confirmed previous dengue virus infection and who were living in an area where dengue is endemic. The CYD-TDV dengue vaccine (Dengvaxia) is a live-attenuated tetravalent vaccine built on a yellow fever vaccine backbone. Its effectiveness is 82% for prevention of symptomatic dengue, 79% for prevention of dengue-associated hospitalizations, and 84% against severe dengue.¹²

Continue to: Dengue viruses...

Dengue viruses (DENV) are transmitted by Aedes mosquitoes. There are 4 serotypes of dengue, and all 4 appear to be circulating in most endemic countries. Clinical disease varies from a mild febrile illness to severe disease. The most common clinical presentation includes sudden onset of fever, headache, retro-orbital pain, myalgia and arthralgia, abdominal pain, and nausea.

The incidence of hepatitis B infection among adults has not declined in recent years and has actually increased in some age groups.

Severe disease includes plasma leakage, shock, respiratory distress, severe bleeding, and organ failure. While severe dengue can occur with a primary infection, a second infection with a different DENV increases the risk of severe dengue. A small increased risk of severe dengue occurs when dengue infection occurs after vaccination in those with no evidence of previous dengue infection. It is felt that the vaccine serves as a primary infection that increases the risk of severe dengue with subsequent infections. This is the reason that the vaccine is recommended only for those with a documented previous dengue infection.

At its June 2021 meeting, the ACIP recommended 3-doses of Dengvaxia, administered at 0, 6, and 12 months, for individuals 9 to 16 years of age who have laboratory confirmation of previous dengue infection and live in endemic areas.¹² These areas include the territories and affiliated states of Puerto Rico, American Samoa, US Virgin Islands, Federated States of Micronesia, Republic of Marshall Islands, and the Republic of Palau. Puerto Rico accounts for 85% of the population of these areas and 95% of reported dengue cases.¹²The reason for the delay between FDA approval and the ACIP recommendation was the need to wait for a readily available, accurate laboratory test to confirm previous dengue infection, which is now available. There are other dengue vaccines in development including 2 live-attenuated, tetravalent vaccine candidates in Phase 3 trials.

In a typical year, the Advisory Committee on Immunization Practices (ACIP) has three 1.5- to 2-day meetings to make recommendations for the use of new and existing vaccines in the US population. However, 2021 was not a typical year. Last year, ACIP held 17 meetings for a total of 127 hours. Most of these were related to vaccines to prevent COVID-19. There are now 3 COVID-19 vaccines authorized for use in the United States: the 2-dose mRNA-based Pfizer-BioNTech/Comirnaty and Moderna COVID-19 vaccines and the single-dose adenovirus, vector-based Janssen (Johnson & Johnson) COVID-19 vaccine.

TABLE 1¹ includes the actions taken by the ACIP from late 2020 through 2021 related to COVID-19 vaccines. All of these recommendations except 1 occurred after the US Food and Drug Administration (FDA) approved the product using an emergency use authorization (EUA). The exception is the recommendation for use of the Pfizer-BioNTech COVID-19 vaccine (BNT162b2) for those ages 16 years and older, which was approved under the normal process 8 months after widespread use under an EUA.

Hepatitis B vaccine now for all nonimmune adults up through 59 years

Since the introduction of hepatitis B (HepB) vaccines in 1980, the incidence of hepatitis B virus (HBV) infections in the United States has been reduced dramatically; there were an estimated 287,000 cases in 1985² and 19,200 in 2014.³ However, the incidence among adults has not declined in recent years and among someage groups has actually increased. Among those ages 40 to 49 years, the rate went from 1.9 per 100,000 in 2011⁴ to 2.7 per 100,000 population in 2019.⁵ In those ages 50 to 59, there was an increase from 1.1 to 1.6 per 100,000 population over the same period of time.^4,5

Recommendations for using HepB vaccine in adults have been based on risk that involves individual behavior, occupation, and medical conditions (TABLE 2⁶). The presence of these risk factors is often unknown to medical professionals, who rarely ask about or document them. And patients can be reluctant to disclose them for fear of being stigmatized. The consequence has been a low rate of vaccination in at-risk adults.

At its November 2021 meeting, ACIP accepted the advice of the Hepatitis Work Group to move to a universal adult recommendation through age 59.⁷ ACIP believed that the incidence of acute infection in those ages 60 and older was too low to merit a universal recommendation. The new recommendation states that all adults through age 59 years who are not immune to HBV through vaccination or prior infection should receive a HepB vaccine series, as should those 60 years and older with a risk factor (TABLE 2⁶). If a patient’s immune status is unknown, ACIP recommends administering the vaccine, as there are no documented harmful effects of doing so in an individual with immunity.

Multiple HepB vaccine products are available for adults. Two are recombinant-based and require 3 doses: Engerix-B (GlaxoSmithKline) and Recombivax HB (Merck). One is recombinant based and requires only 2 doses: Heplisav-B (Dynavax Technologies). A new product recently approved by the FDA, ­PREHEVBRIO (VBI Vaccines), is another recombinant 3-dose option that the ACIP will consider early in 2022. HepB and HepA vaccines can also be co-administered with Twinrix (GlaxoSmithKline).

Pneumococcal vaccines: New PCV vaccines alter prescribing choices

The ACIP recommendations for pneumococcal vaccines in adults have been very confusing, involving 2 vaccines: PCV13 (Prevnar13, Pfizer) and PPSV23 (Pneumovax23, Merck). Both PCV13 and PPSV23 given in series were recommended for immunocompromised patients, but only PPSV23 was recommended for those with chronic medical conditions. For those 65 and older, PPSV23 was recommended for all individuals (including those with no chronic or immunocompromising condition), and PCV13 was recommended for those with immunocompromising conditions. Other adults in this older age group could receive PCV13 based on individual risk and shared clinical decision making.⁸

Continue to: This past year...

This past year, 2 new PCV vaccines were approved by the FDA: PCV15 (Vaxneuvance, Merck) and PCV20 (Prevnar20, Pfizer). While considering these new vaccines, the ACIP re-­assessed its entire approval of pneumococcal vaccines. First, they retained the cutoff for universal pneumococcal vaccination at 65 years. For those younger than 65, they combined chronic medical conditions and immunocompromising conditions into a single at-risk group (TABLE 3⁹). They then issued the same recommendation for older adults and those younger than 65 with risks: to receive a PCV vaccine, either PCV15 or PCV20. If they receive PCV15, it should be followed by PPSV23. PPSV23 is not recommended for those who receive PCV20. Therefore, PPSV23 is no longer routinely recommended for adults unless PCV15 is the PCV of choice.⁹ Clinical guidance on the use of PCV vaccines will be published in early 2022.

Zoster vaccine for younger adults

Recombinant zoster vaccine (RZV) has been licensed and recommended in the United States since 2017 in a 2-dose schedule for adults ages 50 years and older. In the summer of 2021, the FDA expanded the indication for use of RZV to include individuals 18 to 49 years of age who are or will be immunodeficient or immunosuppressed due to known disease or therapy. In October, the ACIP agreed and recommended 2 RZV doses for those 19 years and older in these risk groups (TABLE 4¹⁰).

This recommendation was based on the elevated risk of herpes zoster documented in those with immune-suppressing conditions and therapies. In the conditions studied, the incidence in these younger adults exceeded that for older adults, for whom the vaccine is recommended.¹⁰ There are many immune conditions and immune-suppressing medications. The ACIP Zoster Work Group did not have efficacy and safety information on the use of RZV in each one of them, even though their recommendation includes them all. Many of these patients are under the care of specialists whose specialty societies had been recommending zoster vaccine for their patients, off label, prior to the FDA authorization.

Rabies vaccine is now available in 2-dose schedule

People who should receive rabies pre-exposure prophylaxis (PrEP) with rabies vaccine include laboratory personnel who work with rabies virus, biologists who work with bats, animal care professionals, wildlife biologists, veterinarians, and travelers who may be at risk of encountering rabid dogs. The recommendation has been for 3 doses of rabies vaccine at 0, 7, and 21-28 days. The ACIP voted at its June 2021 meeting to adopt a 2-dose PrEP schedule of 0 and 7 days.¹¹ This will be especially helpful to travelers who want to complete the recommended doses prior to departure. Those who have sustained risk over time can elect to have a third dose after 21 days and before 3 years, or elect to have titers checked. More detailed clinical advice will be published in the CDC’s Morbidity and Mortality Weekly Report in 2022.

Dengue vaccine: New rec for those 9-16 years

In 2019, the FDA approved the first dengue vaccine for use in the United States for children 9 to 16 years old who had laboratory-­confirmed previous dengue virus infection and who were living in an area where dengue is endemic. The CYD-TDV dengue vaccine (Dengvaxia) is a live-attenuated tetravalent vaccine built on a yellow fever vaccine backbone. Its effectiveness is 82% for prevention of symptomatic dengue, 79% for prevention of dengue-associated hospitalizations, and 84% against severe dengue.¹²

Continue to: Dengue viruses...

Dengue viruses (DENV) are transmitted by Aedes mosquitoes. There are 4 serotypes of dengue, and all 4 appear to be circulating in most endemic countries. Clinical disease varies from a mild febrile illness to severe disease. The most common clinical presentation includes sudden onset of fever, headache, retro-orbital pain, myalgia and arthralgia, abdominal pain, and nausea.

The incidence of hepatitis B infection among adults has not declined in recent years and has actually increased in some age groups.

Severe disease includes plasma leakage, shock, respiratory distress, severe bleeding, and organ failure. While severe dengue can occur with a primary infection, a second infection with a different DENV increases the risk of severe dengue. A small increased risk of severe dengue occurs when dengue infection occurs after vaccination in those with no evidence of previous dengue infection. It is felt that the vaccine serves as a primary infection that increases the risk of severe dengue with subsequent infections. This is the reason that the vaccine is recommended only for those with a documented previous dengue infection.

At its June 2021 meeting, the ACIP recommended 3-doses of Dengvaxia, administered at 0, 6, and 12 months, for individuals 9 to 16 years of age who have laboratory confirmation of previous dengue infection and live in endemic areas.¹² These areas include the territories and affiliated states of Puerto Rico, American Samoa, US Virgin Islands, Federated States of Micronesia, Republic of Marshall Islands, and the Republic of Palau. Puerto Rico accounts for 85% of the population of these areas and 95% of reported dengue cases.¹²The reason for the delay between FDA approval and the ACIP recommendation was the need to wait for a readily available, accurate laboratory test to confirm previous dengue infection, which is now available. There are other dengue vaccines in development including 2 live-attenuated, tetravalent vaccine candidates in Phase 3 trials.

In a typical year, the Advisory Committee on Immunization Practices (ACIP) has three 1.5- to 2-day meetings to make recommendations for the use of new and existing vaccines in the US population. However, 2021 was not a typical year. Last year, ACIP held 17 meetings for a total of 127 hours. Most of these were related to vaccines to prevent COVID-19. There are now 3 COVID-19 vaccines authorized for use in the United States: the 2-dose mRNA-based Pfizer-BioNTech/Comirnaty and Moderna COVID-19 vaccines and the single-dose adenovirus, vector-based Janssen (Johnson & Johnson) COVID-19 vaccine.

TABLE 1¹ includes the actions taken by the ACIP from late 2020 through 2021 related to COVID-19 vaccines. All of these recommendations except 1 occurred after the US Food and Drug Administration (FDA) approved the product using an emergency use authorization (EUA). The exception is the recommendation for use of the Pfizer-BioNTech COVID-19 vaccine (BNT162b2) for those ages 16 years and older, which was approved under the normal process 8 months after widespread use under an EUA.

Hepatitis B vaccine now for all nonimmune adults up through 59 years

Since the introduction of hepatitis B (HepB) vaccines in 1980, the incidence of hepatitis B virus (HBV) infections in the United States has been reduced dramatically; there were an estimated 287,000 cases in 1985² and 19,200 in 2014.³ However, the incidence among adults has not declined in recent years and among someage groups has actually increased. Among those ages 40 to 49 years, the rate went from 1.9 per 100,000 in 2011⁴ to 2.7 per 100,000 population in 2019.⁵ In those ages 50 to 59, there was an increase from 1.1 to 1.6 per 100,000 population over the same period of time.^4,5

Recommendations for using HepB vaccine in adults have been based on risk that involves individual behavior, occupation, and medical conditions (TABLE 2⁶). The presence of these risk factors is often unknown to medical professionals, who rarely ask about or document them. And patients can be reluctant to disclose them for fear of being stigmatized. The consequence has been a low rate of vaccination in at-risk adults.

At its November 2021 meeting, ACIP accepted the advice of the Hepatitis Work Group to move to a universal adult recommendation through age 59.⁷ ACIP believed that the incidence of acute infection in those ages 60 and older was too low to merit a universal recommendation. The new recommendation states that all adults through age 59 years who are not immune to HBV through vaccination or prior infection should receive a HepB vaccine series, as should those 60 years and older with a risk factor (TABLE 2⁶). If a patient’s immune status is unknown, ACIP recommends administering the vaccine, as there are no documented harmful effects of doing so in an individual with immunity.

Multiple HepB vaccine products are available for adults. Two are recombinant-based and require 3 doses: Engerix-B (GlaxoSmithKline) and Recombivax HB (Merck). One is recombinant based and requires only 2 doses: Heplisav-B (Dynavax Technologies). A new product recently approved by the FDA, ­PREHEVBRIO (VBI Vaccines), is another recombinant 3-dose option that the ACIP will consider early in 2022. HepB and HepA vaccines can also be co-administered with Twinrix (GlaxoSmithKline).

Pneumococcal vaccines: New PCV vaccines alter prescribing choices

The ACIP recommendations for pneumococcal vaccines in adults have been very confusing, involving 2 vaccines: PCV13 (Prevnar13, Pfizer) and PPSV23 (Pneumovax23, Merck). Both PCV13 and PPSV23 given in series were recommended for immunocompromised patients, but only PPSV23 was recommended for those with chronic medical conditions. For those 65 and older, PPSV23 was recommended for all individuals (including those with no chronic or immunocompromising condition), and PCV13 was recommended for those with immunocompromising conditions. Other adults in this older age group could receive PCV13 based on individual risk and shared clinical decision making.⁸

Continue to: This past year...

This past year, 2 new PCV vaccines were approved by the FDA: PCV15 (Vaxneuvance, Merck) and PCV20 (Prevnar20, Pfizer). While considering these new vaccines, the ACIP re-­assessed its entire approval of pneumococcal vaccines. First, they retained the cutoff for universal pneumococcal vaccination at 65 years. For those younger than 65, they combined chronic medical conditions and immunocompromising conditions into a single at-risk group (TABLE 3⁹). They then issued the same recommendation for older adults and those younger than 65 with risks: to receive a PCV vaccine, either PCV15 or PCV20. If they receive PCV15, it should be followed by PPSV23. PPSV23 is not recommended for those who receive PCV20. Therefore, PPSV23 is no longer routinely recommended for adults unless PCV15 is the PCV of choice.⁹ Clinical guidance on the use of PCV vaccines will be published in early 2022.

Zoster vaccine for younger adults

Recombinant zoster vaccine (RZV) has been licensed and recommended in the United States since 2017 in a 2-dose schedule for adults ages 50 years and older. In the summer of 2021, the FDA expanded the indication for use of RZV to include individuals 18 to 49 years of age who are or will be immunodeficient or immunosuppressed due to known disease or therapy. In October, the ACIP agreed and recommended 2 RZV doses for those 19 years and older in these risk groups (TABLE 4¹⁰).

This recommendation was based on the elevated risk of herpes zoster documented in those with immune-suppressing conditions and therapies. In the conditions studied, the incidence in these younger adults exceeded that for older adults, for whom the vaccine is recommended.¹⁰ There are many immune conditions and immune-suppressing medications. The ACIP Zoster Work Group did not have efficacy and safety information on the use of RZV in each one of them, even though their recommendation includes them all. Many of these patients are under the care of specialists whose specialty societies had been recommending zoster vaccine for their patients, off label, prior to the FDA authorization.

Rabies vaccine is now available in 2-dose schedule

People who should receive rabies pre-exposure prophylaxis (PrEP) with rabies vaccine include laboratory personnel who work with rabies virus, biologists who work with bats, animal care professionals, wildlife biologists, veterinarians, and travelers who may be at risk of encountering rabid dogs. The recommendation has been for 3 doses of rabies vaccine at 0, 7, and 21-28 days. The ACIP voted at its June 2021 meeting to adopt a 2-dose PrEP schedule of 0 and 7 days.¹¹ This will be especially helpful to travelers who want to complete the recommended doses prior to departure. Those who have sustained risk over time can elect to have a third dose after 21 days and before 3 years, or elect to have titers checked. More detailed clinical advice will be published in the CDC’s Morbidity and Mortality Weekly Report in 2022.

Dengue vaccine: New rec for those 9-16 years

In 2019, the FDA approved the first dengue vaccine for use in the United States for children 9 to 16 years old who had laboratory-­confirmed previous dengue virus infection and who were living in an area where dengue is endemic. The CYD-TDV dengue vaccine (Dengvaxia) is a live-attenuated tetravalent vaccine built on a yellow fever vaccine backbone. Its effectiveness is 82% for prevention of symptomatic dengue, 79% for prevention of dengue-associated hospitalizations, and 84% against severe dengue.¹²

Continue to: Dengue viruses...

Dengue viruses (DENV) are transmitted by Aedes mosquitoes. There are 4 serotypes of dengue, and all 4 appear to be circulating in most endemic countries. Clinical disease varies from a mild febrile illness to severe disease. The most common clinical presentation includes sudden onset of fever, headache, retro-orbital pain, myalgia and arthralgia, abdominal pain, and nausea.

The incidence of hepatitis B infection among adults has not declined in recent years and has actually increased in some age groups.

Severe disease includes plasma leakage, shock, respiratory distress, severe bleeding, and organ failure. While severe dengue can occur with a primary infection, a second infection with a different DENV increases the risk of severe dengue. A small increased risk of severe dengue occurs when dengue infection occurs after vaccination in those with no evidence of previous dengue infection. It is felt that the vaccine serves as a primary infection that increases the risk of severe dengue with subsequent infections. This is the reason that the vaccine is recommended only for those with a documented previous dengue infection.

At its June 2021 meeting, the ACIP recommended 3-doses of Dengvaxia, administered at 0, 6, and 12 months, for individuals 9 to 16 years of age who have laboratory confirmation of previous dengue infection and live in endemic areas.¹² These areas include the territories and affiliated states of Puerto Rico, American Samoa, US Virgin Islands, Federated States of Micronesia, Republic of Marshall Islands, and the Republic of Palau. Puerto Rico accounts for 85% of the population of these areas and 95% of reported dengue cases.¹²The reason for the delay between FDA approval and the ACIP recommendation was the need to wait for a readily available, accurate laboratory test to confirm previous dengue infection, which is now available. There are other dengue vaccines in development including 2 live-attenuated, tetravalent vaccine candidates in Phase 3 trials.

CASE

Jack Z, a 75-year-old man with well-controlled hypertension, diabetes controlled by diet, and atrial fibrillation (AF) presents to the family medicine clinic to establish care with you after moving to the community from out of town.

The patient describes a 1-year history of AF. He provides you with an echocardiography report from 6 months ago that shows no evidence of structural heart disease. He takes lisinopril, to control blood pressure; an anticoagulant; a beta-blocker; and amiodarone for rhythm control. Initially, he took flecainide, which was ineffective for rhythm control, before being switched to amiodarone. He had 2 cardioversion procedures, each time after episodes of symptoms. He does not smoke or drink alcohol.

Mr. Z describes worsening palpitations and shortness of breath over the past 9 months. Symptoms now include episodes of exertional fatigue, even when he is not having palpitations. Prior to the episodes of worsening symptoms, he tells you that he lived a “fairly active” life, golfing twice a week.

The patient’s previous primary care physician had encouraged him to talk to his cardiologist about “other options” for managing AF, because levels of his liver enzymes had started to rise (a known adverse effect of amiodarone¹) when measured 3 months ago. He did not undertake that conversation, but asks you now about other treatments for AF.

Atrial fibrillation is the most common sustained cardiac arrhythmia, characterized by discordant electrical activation of the atria due to structural or electrophysiological abnormalities, or both. The disorder is associated with an increased rate of stroke and heart failure and is independently associated with a 1.5- to 2-fold risk of all-cause mortality.²

In this article, we review the pathophysiology of AF; management, including the role of, and indications for, catheter ablation; and patient- and disease-related factors associated with ablation (including odds of success, complications, risk of recurrence, and continuing need for thromboprophylaxis) that family physicians should consider when contemplating referral to a cardiologist or electrophysiologist for catheter ablation for AF.

What provokes AF?

AF is thought to occur as a result of an interaction among 3 phenomena:

• enhanced automaticity of abnormal atrial tissue
• triggered activity of ectopic foci within 1 or more pulmonary veins, lying within the left atrium
• re-entry, in which there is propagation of electrical impulses from an ectopic beat through another pathway.

Continue to: In patients who progress...

In patients who progress from paroxysmal to persistent AF (see “Subtypes,” below), 2 distinct pathways, facilitated by the presence of abnormal tissue, continuously activate one another, thus maintaining the arrhythmia. Myocardial tissue in the pulmonary veins is responsible for most ectopic electrical impulses in patients with drug-refractory AF (see “Rhythm control”).

Subtypes. For the purpose of planning treatment, AF is classified as:

• Paroxysmal. Terminates spontaneously or with intervention ≤ 7 days after onset.
• Persistent. Continuous and sustained for > 7 days.
• Longstanding persistent. Continuous for > 12 months.
• Permanent. The patient and physician accept that there will be no further attempt to restore or maintain sinus rhythm.

Goals of treatment

Primary management goals in patients with AF are 2-fold: control of symptoms and prevention of thromboembolism. A patient with new-onset AF who presents acutely with inadequate rate control and hemodynamic compromise requires urgent assessment to determine the cause of the arrhythmia and need for cardioversion.³ A symptomatic patient with AF who does not have high-risk features (eg, valvular heart disease, mechanical valves) might be a candidate for rhythm control in addition to rate control.^3,4

Rate control. After evaluation in the hospital, a patient who has a rapid ventricular response but remains hemodynamically stable, without evidence of heart failure, should be initiated on a rate-controlling medication, such as a beta-blocker or nondihydropyridine calcium-channel blocker. A resting heart rate goal of < 80 beats per minute (bpm) is recommended for a symptomatic patient with AF. The heart rate goal can be relaxed, to < 110 bpm, in an asymptomatic patient with preserved left ventricular function.^5,6

Rhythm control, indicated in patients who remain symptomatic on rate-controlling medication, can be achieved either with an antiarrhythmic drug (AAD) or by catheter ablation.^4,5 In stable patients, rhythm control should be considered only after a thorough work-up for a reversible cause of AF, and can be achieved with an oral AAD or, in select patients, through catheter ablation (TABLE 1^3,6). Other indications for chronic rhythm control include treatment of patients with ­tachycardia-induced cardiomyopathy.⁵

Continuing symptoms when taking rate-controlling medication for atrial fibrillation is one indication for rhythm control with an antiarrhythmic drug or by catheter ablation.

A major study that documented the benefit of early rhythm control evaluated long-term outcomes in 2789 patients with AF who were undergoing catheter ablation.⁷ Patients were randomized to early rhythm control (catheter ablation or AAD) or “usual care”—ie, in this study, rhythm control limited to symptomatic patients. Primary outcomes were death from cardiovascular causes, stroke, and hospitalization with worsening heart failure or acute coronary syndrome. A first primary outcome event occurred in 249 patients (3.9/100 person-years) assigned to early rhythm control, compared to 316 (5.0 per 100 person-years) in the group assigned to usual care.

The study was terminated early (after 5.1 years) because of overwhelming evidence of efficacy (number need to treat = 7). Although early rhythm control was obtained through both catheter ablation and AAD (hazard ratio [HR] = 0.79; 96% CI, 0.66-0.94; P = .005), success was attributed to the use of catheter ablation for a rhythm-control strategy and its use among patients whose AF was present for < 1 year. Most patients in both treatment groups continued to receive anticoagulation, rate control, and optimization of cardiovascular risk.⁷

Continue to: Notably, direct studies...

Notably, direct studies comparing ablation and AAD have not confirmed the benefit of ablation over AAD in outcomes of all-cause mortality, bleeding, stroke, or cardiac arrest over a 5-year period.⁸

Adverse effects and mortality outcomes with AAD. Concern over using AAD for rhythm control is based mostly on adverse effects and long-term (1-year) mortality outcomes. Long-term AAD therapy has been shown to decrease the recurrence of AF—but without evidence to suggest other mortality benefits.

A meta-analysis of 59 randomized controlled trials reviewed 20,981 patients receiving AAD (including quinidine, disopyramide, propafenone, flecainide, metoprolol, amiodarone, dofetilide, dronedarone, and sotalol) for long-term effects on death, stroke, adverse reactions, and recurrence of AF.⁹ Findings at 10 months suggest that:

• Compared to placebo, amiodarone and sotalol increased the risk of all-cause mortality during the study period.
• There was minimal difference in mortality among patients taking dofetilide or dronedarone, compared to placebo.
• There were insufficient data to draw conclusions about the effect of disopyramide, flecainide, and propafenone on mortality.

Before starting a patient on AAD, the risk of arrhythmias and the potential for these agents to cause toxicity and adverse events should always be discussed.

CASE

You tell Mr. Z that you need to know the status of his comorbidities to make a recommendation about “other” management options, and proceed to take a detailed history.

Recent history. Mr. Z reveals that “today is a good day”: He has had “only 1” episode of palpitations, which resolved on its own. The previous episode, he explains, was 3 days ago, when palpitations were associated with lightheadedness and shortness of breath. He denies chest pains or swelling of the legs.

Physical exam. The patient appears spry, comfortable, and in no acute distress. Vital signs are within normal limits. A body mass index of 28.4 puts him in the “overweight” category. His blood pressure is 118/75 mm Hg.

Continue to: Cardiac examination...

Cardiac examination is significant for an irregular rhythm without murmurs, rubs, or gallops. His lungs are clear bilaterally; his abdomen is soft and nondistended. His extremities show no edema.

Testing. You obtain an electrocardiogram, which demonstrates a controlled ventricular rate of 88 bpm and AF. You order a complete blood count, comprehensive metabolic panel, tests of hemoglobin A1C and thyroid-stimulating hormone, lipid panel, echocardiogram, and a chest radiograph.

Results. The chest radiograph is negative for an acute cardiopulmonary process; cardiac size is normal. Aspartate aminotransferase and alanine aminotransferase levels are higher than twice the normal limit. The echocardiogram reveals an estimated left ventricular ejection fraction of 55% to 60%; no structural abnormalities are noted.

In which AF patients is catheter ablation indicated?

Ablation is recommended for select patients (TABLE 1^3,6) with symptomatic paroxysmal AF that is refractory to AAD or who are intolerant of AAD.^3,6 It is a reasonable first-line therapy for high-performing athletes in whom AAD would affect athletic performance.^3,10 It is also a reasonable option in select patients > 75 years and as an alternative to AAD therapy.³ Finally, catheter ablation should be considered in symptomatic patients with longstanding persistent AF and congestive heart failure, with or without reduced left ventricular ejection fraction.³

CASE

You inform Mr. Z that his symptoms are likely a result of symptomatic paroxysmal AF, which was refractory to flecainide and amiodarone, and that his abnormal liver function test results preclude continued use of amiodarone. You propose Holter monitoring to correlate timing of symptoms with the arrhythmia, but he reports this has been done, and the correlation confirmed, by his previous physician.

You explain that, because the diagnosis of symptomatic paroxysmal AF refractory to AADs has been confirmed, he is categorized as a patient who might benefit from catheter ablation, based on:

• the type of AF (ie, paroxysmal AF is associated with better ablation outcomes)
• persistent symptoms that are refractory to AADs
• his intolerance of AAD
• the length of time since onset of symptoms.

Mr. Z agrees to consider your recommendation.

Continue to: What are the benefits of catheter ablation?

Ablation can be achieved through radiofrequency (RF) ablation, cryoablation, or newer, laser-based balloon ablation. Primary outcomes used to determine the success of any options for performing ablation include mortality, stroke, and hospitalization. Other endpoints include maintenance of sinus rhythm, freedom from AF, reduction in AF burden (estimated through patients’ report of symptoms, recurrence rate, need for a second ablation procedure, and serial long-term monitoring through an implantable cardiac monitoring device), quality of life, and prevention of AF progression.³

Patient and disease variables (TABLE 2^11-13). The success rate of catheter ablation, defined as freedom from either symptomatic or asymptomatic episodes of AF, is dependent on several factors,^3,14 including:

• type of AF (paroxysmal or persistent)
• duration and degree of symptoms
• age
• sex
• comorbidities, including heart failure and structural heart or lung disease.

Overall, in patients with paroxysmal AF, an estimated 75% are symptom free 1 year after ablation.¹⁵ Patients with persistent and longstanding persistent AF experience a lower success rate.

Ablation is recommended in patients with symptomatic paroxysmal atrial fibrillation that is refractory to antiarrhythmics or when they are intolerant of these drugs.

RF catheter ablation has demonstrated superiority to AAD in reducing the need for cardioversion (relative risk [RR] = 0.62; 95% CI, 0.47-0.82) and cardiac-related hospitalization (RR = 0.27; 95% CI, 0.10-0.72;) at 12 months in patients with nonparoxysmal AF (persistent or longstanding persistent).¹⁶

Effect on mortality. Among patients with heart failure with reduced ejection fraction, long-term studies of cardiovascular outcomes 5 years post ablation concluded that ablation is associated with a decrease in all-cause mortality (RR = 0.69; 95% CI, 0.54-0.88; P = .003) and a reduction in hospitalization (RR = 0.62; 95% CI, 0.47-0.82; P = .0006); younger (< 65 years) and male patients derive greater benefit.^6,17 Indications for ablation in patients with heart failure are similar to those in patients without heart failure; ablation can therefore be considered for select heart failure patients who remain symptomatic or for whom AAD has failed.³

Older patients. Ablation can be considered for patients > 75 years with symptomatic paroxysmal AF refractory to AAD or who are intolerant of AAD.³ A study that assessed the benefit of catheter ablation reviewed 587 older (> 75 years) patients with AF, of whom 324 were eligible for ablation. Endpoints were maintenance of sinus rhythm, stroke, death, and major bleeding. Return to normal sinus rhythm was an independent factor, associated with a decrease in the risk of mortality among all patient groups that underwent ablation (HR = 0.36; 95% CI, 0.2-0.63; P = .0005). Age > 75 years (HR = 1.09; 95% CI, 1.01-1.16; P > .02) and depressed ejection fraction < 40% (HR = 2.38; 95% CI, 1.28-4.4; P = .006) were determined to be unfavorable parameters for survival.¹⁸

Complications and risks

Complications of catheter ablation for AF, although infrequent, can be severe (TABLE 3³). Early mortality, defined as death during initial admission or 30-day readmission, occurs in approximately 0.5% of cases; half of deaths take place during readmission.¹¹

Continue to: Complications vary...

Complications vary, based on the type and site of ablation.^19,20 Cardiac tamponade or perforation, the most life-threatening complications, taken together occur in an estimated 1.9% of patients (odds ratio [OR] = 2.98; 95% CI, 1.36-6.56; P = .007).¹¹ Other in-hospital complications independently predictive of death include any cardiac complications (OR = 12.8; 95% CI, 6.86 to 23.8; P < .001) and neurologic complications (cerebrovascular accident and transient ischemic attack) (OR = 8.72; 95% CI, 2.71-28.1; P < .001).

Other complications that do not cause death but might prolong the hospital stay include pericarditis without effusion, anesthesia-related complications, and vascular-access complications. Patients whose ablation is performed at an institution where the volume of ablations is low are also at higher risk of early mortality (OR = 2.35; 95% CI, 1.33-4.15; P = .003).¹⁶

Recurrence is common (TABLE 2^11-13). Risk of recurrence following ablation is significant; early (within 3 months after ablation) recurrence is seen in 50% of patients.^21,22 However, this is a so-called "blanking period"—ie, a temporary period of inflammatory and proarrhythmic changes that are not predictors of later recurrence. The 5-year post-ablation recurrence rate is approximately 25.5%; longstanding persistent and persistent AF and the presence of comorbidities are major risk factors for recurrence.^13,23

Recurrence is also associated with the type of procedure; pulmonary vein isolation, alone or in combination with another type of procedure, results in higher long-term success.^21,23

Other variables affect outcome (TABLE 2^11-13). Following AF ablation, patients with nonparoxysmal AF at baseline, advanced age, sleep apnea and obesity, left atrial enlargement, and any structural heart disease tend to have a poorer long-term (5-year) outcome (ie, freedom from extended episodes of AF).^3,13,23,24

Patients who undergo repeat procedures have higher arrhythmia-free survival; the highest ablation success rate is for patients with paroxysmal AF.^13,23

Exposure to ionizing radiation. Fluoroscopy is required for multiple components of atrial mapping and ablation during RF ablation, including navigation, visualization, and monitoring of catheter placement. Patients undergoing this particular procedure therefore receive significant exposure to ionizing radiation. A reduction in, even complete elimination of, fluoroscopy has been achieved with:

• nonfluoroscopic 3-dimensional mapping systems²⁵
• intracardiac echocardiography, which utilizes ultrasonographic imaging as the primary visual mode for tracking and manipulating the catheter
• robotic guided navigation.^26-28

Continue to: CASE

CASE

At his return visit, Mr. Z says that he is concerned about, first, undergoing catheter ablation at his age and, second, the risks associated with the procedure. You explain that it is true that ablation is ideal in younger patients who have minimal comorbidities and that the risk of complications increases with age—but that there is no cutoff or absolute age contraindication to ablation.

You tell Mr. Z that you will work with him on risk-factor modification in anticipation of ablation. You also assure him that the decision whether to ablate must be a joint one—between him and a cardiologist experienced both in electrophysiology and in performing this highly technical procedure. And you explain that a highly practiced specialist can identify Mr. Z’s risk factors that might make ablation more difficult to perform and affect the long-term outcome.

With Mr. Z’s agreement, you screen for sleep apnea and start him on a lifestyle modification plan to achieve a more ideal weight, explaining that the risk of recurrence of AF after catheter ablation is increased by obesity and sleep apnea, in addition to age. You explain that, based on his CHA₂DS₂–VASc (congestive heart failure; hypertension; age, ≥ 75 years; diabetes; prior stroke, transient ischemic attack, or thromboembolism; vascular disease; age, 65 to 74 years; sex category) score of 3, he will remain on anticoagulation whether or not he has the ablation.

You refer the patient to the nearest high-volume cardiac ablation center.

Last, you caution Mr. Z that, based on his lipid levels, his 10-year risk of heart disease or stroke is elevated. You recommend treatment with a statin agent while he continues his other medications.

Delivering energy to myocardium

Myocardial tissue in pulmonary veins is responsible for most ectopic electrical impulses in patients with drug-refractory AF. The goal of catheter ablation in AF is destruction (scarring) of tissue that is the source of abnormal vein potentials.¹⁵

How RF ablation works. Ablation is most commonly performed using RF energy, a high-frequency form of electrical energy. Electrophysiology studies are carried out at the time of ablation by percutaneous, fluoroscopically guided insertion of 2 to 5 catheters, usually through the femoral or internal jugular vein, which are then positioned within several areas of the heart—usually, the right atrium, bundle of His, right ventricle, and coronary sinus.

Continue to: Electrical current...

Successful ablation is defined as freedom from symptomatic or asymptomatic AF episodes, and depends on AF type; duration and degree of symptoms; and age, sex, and comorbidities.

Electrical current is applied through the catheters from an external generator to stimulate the myocardium and thus determine its electrophysiologic properties. The anatomic and electrical activity of the left atrium and pulmonary veins is then identified, a technique known as electro-anatomical mapping (FIGURE). After arrhythmogenic myocardial tissue is mapped, ablation is carried out with RF energy through the catheter to the pathogenic myocardium from which arrhythmias are initiated or conducted. The result is thermal destruction of tissue and creation of small, shallow lesions that vary in size with the type of catheter and the force of contact pressure applied.^3,29

Other energy sources used in catheter ablation include cryothermal energy, which utilizes liquid nitrous oxide under pressure through a cryocatheter or cryoballoon catheter. Application of cryothermal energy freezes tissue and disrupts cell membranes and any electrical activity. Cryoballoon ablation has been shown to be similarly safe and efficacious as RF ablation in patients with paroxysmal AF.^30,31

Newer laser-based balloon ablations are performed under ultrasonographic guidance and utilize arcs of laser energy delivered to the pathogenic myocardium.³

Thromboembolism prophylaxis

Oral anticoagulation to decrease the risk of stroke is initiated in all patients with AF, based on a thromboembolic risk profile determined by their CHA₂DS₂–VASc score, with anticoagulation recommended when the score is ≥ 2 in men and ≥ 3 in women. Options for anticoagulation include warfarin and one of the novel oral anticoagulants dabigatran, apixaban, rivaroxaban, and edoxaban.⁴ Recommendations are as follows³:

• For patients with a CHA₂DS₂–VASc score of ≥ 2 (men) or ≥ 3 (women), anticoagulation should be continued indefinitely, regardless of how successful the ablation procedure is.
• When patients choose to discontinue anticoagulation, they should be counseled in detail about the risk of doing so. The continued need for frequent arrhythmia monitoring should be emphasized.

The route from primary careto catheter ablation

Perform a thorough evaluation. Patients who present to you with palpitations should first undergo a routine workup for AF, followed by confirmation of the diagnosis. Exclude structural heart disease with echocardiography. Undertake monitoring, which is essential to determine whether symptoms are a reflection of the arrhythmia, using noncontinuous or continuous electrocardiographic (EKG) monitoring. Noncontinuous detection devices include:

• scheduled or symptom-initiated EKG
• a Holter monitor, worn for at least 24 hours and as long as 7 days
• trans-telephonic recordings and patient- or automatically activated devices
• an external loop recorder.³²

Continuous EKG monitoring is more permanent (≥ 12 months). This is usually achieved through an implantable loop powered by a battery that lasts as long as 3 years.³

Ablation: Yes or no? Ablation is not recommended to avoid anticoagulation or when anticoagulation is contraindicated.⁵ With regard to specific patient criteria, the ideal patient:

• is symptomatic
• has failed AAD therapy
• does not have pulmonary disease
• has a normal or mildly dilated left atrium or normal or mildly reduced left ventricular ejection fraction.⁵

Continue to: There is no absolute age...

There is no absolute age or comorbidity contraindication to ablation. The patient should be referred to a cardiologist who has received appropriate training in electrophysiology, to identify comorbidities that (1) increase the technical difficulty of the procedure and baseline risk and (2) affect long-term outcome,¹² and who performs the procedure in a center that has considerable experience with catheter ablation.³³

Once the decision is made to perform ablation, you can provide strategies that optimize the outcome (freedom from AF episodes). Those tactics include weight loss and screening evaluation and, if indicated, treatment for sleep apnea.³

Protocol. Prior to the procedure, the patient fasts overnight; they might be asked to taper or discontinue cardiac medications that have electrophysiologic effects. Studies suggest a low risk of bleeding associated with catheter ablation; anticoagulation should therefore continue uninterrupted for patients undergoing catheter ablation for AF^3,4,34,35; however, this practice varies with the cardiologist or electrophysiologist performing ablation.

Patients whose ablation is performed at an institution where the volume of such procedures is low are at higher risk of early mortality.

Because of the length and complexity of the procedure, electro-anatomical mapping and ablation are conducted with the patient under general anesthesia.³ The patient is kept supine, and remains so for 2 to 4 hours afterward to allow for hemostasis at puncture sites.³

Patients might be monitored overnight, although same-day catheter ablation has been shown to be safe and cost-effective in select patients.^36,37 Post ablation, patients follow up with the cardiologist and electrophysiologist. Long-term arrhythmia monitoring is required.³ Anticoagulation is continued for at least 2 months, and is discontinued based on the patient’s risk for stroke, utilizing their CHA₂DS₂–VASc score.^3,4

CASE

At Mr. Z’s 6-month primary care follow-up, he confirms what has been reported to you as the referring physician: He had a successful catheter ablation and continues to have regular follow-up monitoring with the cardiologist. He is no longer taking amiodarone.

At this visit, he reports no recurrence of AF-associated symptoms or detectable AF on cardiac monitoring. He has lost 8 lbs. You counsel to him to continue to maintain a healthy lifestyle.

CORRESPONDENCE
Amimi S. Osayande MD, FAAFP, Northside-Gwinnett Family Medicine Residency Program, Strickland Family Medicine Center, 665 Duluth Highway, Suite 501, Lawrenceville, GA 30046; [email protected]

CASE

Jack Z, a 75-year-old man with well-controlled hypertension, diabetes controlled by diet, and atrial fibrillation (AF) presents to the family medicine clinic to establish care with you after moving to the community from out of town.

The patient describes a 1-year history of AF. He provides you with an echocardiography report from 6 months ago that shows no evidence of structural heart disease. He takes lisinopril, to control blood pressure; an anticoagulant; a beta-blocker; and amiodarone for rhythm control. Initially, he took flecainide, which was ineffective for rhythm control, before being switched to amiodarone. He had 2 cardioversion procedures, each time after episodes of symptoms. He does not smoke or drink alcohol.

Mr. Z describes worsening palpitations and shortness of breath over the past 9 months. Symptoms now include episodes of exertional fatigue, even when he is not having palpitations. Prior to the episodes of worsening symptoms, he tells you that he lived a “fairly active” life, golfing twice a week.

The patient’s previous primary care physician had encouraged him to talk to his cardiologist about “other options” for managing AF, because levels of his liver enzymes had started to rise (a known adverse effect of amiodarone¹) when measured 3 months ago. He did not undertake that conversation, but asks you now about other treatments for AF.

Atrial fibrillation is the most common sustained cardiac arrhythmia, characterized by discordant electrical activation of the atria due to structural or electrophysiological abnormalities, or both. The disorder is associated with an increased rate of stroke and heart failure and is independently associated with a 1.5- to 2-fold risk of all-cause mortality.²

In this article, we review the pathophysiology of AF; management, including the role of, and indications for, catheter ablation; and patient- and disease-related factors associated with ablation (including odds of success, complications, risk of recurrence, and continuing need for thromboprophylaxis) that family physicians should consider when contemplating referral to a cardiologist or electrophysiologist for catheter ablation for AF.

What provokes AF?

AF is thought to occur as a result of an interaction among 3 phenomena:

• enhanced automaticity of abnormal atrial tissue
• triggered activity of ectopic foci within 1 or more pulmonary veins, lying within the left atrium
• re-entry, in which there is propagation of electrical impulses from an ectopic beat through another pathway.

Continue to: In patients who progress...

In patients who progress from paroxysmal to persistent AF (see “Subtypes,” below), 2 distinct pathways, facilitated by the presence of abnormal tissue, continuously activate one another, thus maintaining the arrhythmia. Myocardial tissue in the pulmonary veins is responsible for most ectopic electrical impulses in patients with drug-refractory AF (see “Rhythm control”).

Subtypes. For the purpose of planning treatment, AF is classified as:

• Paroxysmal. Terminates spontaneously or with intervention ≤ 7 days after onset.
• Persistent. Continuous and sustained for > 7 days.
• Longstanding persistent. Continuous for > 12 months.
• Permanent. The patient and physician accept that there will be no further attempt to restore or maintain sinus rhythm.

Goals of treatment

Primary management goals in patients with AF are 2-fold: control of symptoms and prevention of thromboembolism. A patient with new-onset AF who presents acutely with inadequate rate control and hemodynamic compromise requires urgent assessment to determine the cause of the arrhythmia and need for cardioversion.³ A symptomatic patient with AF who does not have high-risk features (eg, valvular heart disease, mechanical valves) might be a candidate for rhythm control in addition to rate control.^3,4

Rate control. After evaluation in the hospital, a patient who has a rapid ventricular response but remains hemodynamically stable, without evidence of heart failure, should be initiated on a rate-controlling medication, such as a beta-blocker or nondihydropyridine calcium-channel blocker. A resting heart rate goal of < 80 beats per minute (bpm) is recommended for a symptomatic patient with AF. The heart rate goal can be relaxed, to < 110 bpm, in an asymptomatic patient with preserved left ventricular function.^5,6

Rhythm control, indicated in patients who remain symptomatic on rate-controlling medication, can be achieved either with an antiarrhythmic drug (AAD) or by catheter ablation.^4,5 In stable patients, rhythm control should be considered only after a thorough work-up for a reversible cause of AF, and can be achieved with an oral AAD or, in select patients, through catheter ablation (TABLE 1^3,6). Other indications for chronic rhythm control include treatment of patients with ­tachycardia-induced cardiomyopathy.⁵

Continuing symptoms when taking rate-controlling medication for atrial fibrillation is one indication for rhythm control with an antiarrhythmic drug or by catheter ablation.

A major study that documented the benefit of early rhythm control evaluated long-term outcomes in 2789 patients with AF who were undergoing catheter ablation.⁷ Patients were randomized to early rhythm control (catheter ablation or AAD) or “usual care”—ie, in this study, rhythm control limited to symptomatic patients. Primary outcomes were death from cardiovascular causes, stroke, and hospitalization with worsening heart failure or acute coronary syndrome. A first primary outcome event occurred in 249 patients (3.9/100 person-years) assigned to early rhythm control, compared to 316 (5.0 per 100 person-years) in the group assigned to usual care.

The study was terminated early (after 5.1 years) because of overwhelming evidence of efficacy (number need to treat = 7). Although early rhythm control was obtained through both catheter ablation and AAD (hazard ratio [HR] = 0.79; 96% CI, 0.66-0.94; P = .005), success was attributed to the use of catheter ablation for a rhythm-control strategy and its use among patients whose AF was present for < 1 year. Most patients in both treatment groups continued to receive anticoagulation, rate control, and optimization of cardiovascular risk.⁷

Continue to: Notably, direct studies...

Notably, direct studies comparing ablation and AAD have not confirmed the benefit of ablation over AAD in outcomes of all-cause mortality, bleeding, stroke, or cardiac arrest over a 5-year period.⁸

Adverse effects and mortality outcomes with AAD. Concern over using AAD for rhythm control is based mostly on adverse effects and long-term (1-year) mortality outcomes. Long-term AAD therapy has been shown to decrease the recurrence of AF—but without evidence to suggest other mortality benefits.

A meta-analysis of 59 randomized controlled trials reviewed 20,981 patients receiving AAD (including quinidine, disopyramide, propafenone, flecainide, metoprolol, amiodarone, dofetilide, dronedarone, and sotalol) for long-term effects on death, stroke, adverse reactions, and recurrence of AF.⁹ Findings at 10 months suggest that:

• Compared to placebo, amiodarone and sotalol increased the risk of all-cause mortality during the study period.
• There was minimal difference in mortality among patients taking dofetilide or dronedarone, compared to placebo.
• There were insufficient data to draw conclusions about the effect of disopyramide, flecainide, and propafenone on mortality.

Before starting a patient on AAD, the risk of arrhythmias and the potential for these agents to cause toxicity and adverse events should always be discussed.

CASE

You tell Mr. Z that you need to know the status of his comorbidities to make a recommendation about “other” management options, and proceed to take a detailed history.

Recent history. Mr. Z reveals that “today is a good day”: He has had “only 1” episode of palpitations, which resolved on its own. The previous episode, he explains, was 3 days ago, when palpitations were associated with lightheadedness and shortness of breath. He denies chest pains or swelling of the legs.

Physical exam. The patient appears spry, comfortable, and in no acute distress. Vital signs are within normal limits. A body mass index of 28.4 puts him in the “overweight” category. His blood pressure is 118/75 mm Hg.

Continue to: Cardiac examination...

Cardiac examination is significant for an irregular rhythm without murmurs, rubs, or gallops. His lungs are clear bilaterally; his abdomen is soft and nondistended. His extremities show no edema.

Testing. You obtain an electrocardiogram, which demonstrates a controlled ventricular rate of 88 bpm and AF. You order a complete blood count, comprehensive metabolic panel, tests of hemoglobin A1C and thyroid-stimulating hormone, lipid panel, echocardiogram, and a chest radiograph.

Results. The chest radiograph is negative for an acute cardiopulmonary process; cardiac size is normal. Aspartate aminotransferase and alanine aminotransferase levels are higher than twice the normal limit. The echocardiogram reveals an estimated left ventricular ejection fraction of 55% to 60%; no structural abnormalities are noted.

In which AF patients is catheter ablation indicated?

Ablation is recommended for select patients (TABLE 1^3,6) with symptomatic paroxysmal AF that is refractory to AAD or who are intolerant of AAD.^3,6 It is a reasonable first-line therapy for high-performing athletes in whom AAD would affect athletic performance.^3,10 It is also a reasonable option in select patients > 75 years and as an alternative to AAD therapy.³ Finally, catheter ablation should be considered in symptomatic patients with longstanding persistent AF and congestive heart failure, with or without reduced left ventricular ejection fraction.³

CASE

You inform Mr. Z that his symptoms are likely a result of symptomatic paroxysmal AF, which was refractory to flecainide and amiodarone, and that his abnormal liver function test results preclude continued use of amiodarone. You propose Holter monitoring to correlate timing of symptoms with the arrhythmia, but he reports this has been done, and the correlation confirmed, by his previous physician.

You explain that, because the diagnosis of symptomatic paroxysmal AF refractory to AADs has been confirmed, he is categorized as a patient who might benefit from catheter ablation, based on:

• the type of AF (ie, paroxysmal AF is associated with better ablation outcomes)
• persistent symptoms that are refractory to AADs
• his intolerance of AAD
• the length of time since onset of symptoms.

Mr. Z agrees to consider your recommendation.

Continue to: What are the benefits of catheter ablation?

Ablation can be achieved through radiofrequency (RF) ablation, cryoablation, or newer, laser-based balloon ablation. Primary outcomes used to determine the success of any options for performing ablation include mortality, stroke, and hospitalization. Other endpoints include maintenance of sinus rhythm, freedom from AF, reduction in AF burden (estimated through patients’ report of symptoms, recurrence rate, need for a second ablation procedure, and serial long-term monitoring through an implantable cardiac monitoring device), quality of life, and prevention of AF progression.³

Patient and disease variables (TABLE 2^11-13). The success rate of catheter ablation, defined as freedom from either symptomatic or asymptomatic episodes of AF, is dependent on several factors,^3,14 including:

• type of AF (paroxysmal or persistent)
• duration and degree of symptoms
• age
• sex
• comorbidities, including heart failure and structural heart or lung disease.

Overall, in patients with paroxysmal AF, an estimated 75% are symptom free 1 year after ablation.¹⁵ Patients with persistent and longstanding persistent AF experience a lower success rate.

Ablation is recommended in patients with symptomatic paroxysmal atrial fibrillation that is refractory to antiarrhythmics or when they are intolerant of these drugs.

RF catheter ablation has demonstrated superiority to AAD in reducing the need for cardioversion (relative risk [RR] = 0.62; 95% CI, 0.47-0.82) and cardiac-related hospitalization (RR = 0.27; 95% CI, 0.10-0.72;) at 12 months in patients with nonparoxysmal AF (persistent or longstanding persistent).¹⁶

Effect on mortality. Among patients with heart failure with reduced ejection fraction, long-term studies of cardiovascular outcomes 5 years post ablation concluded that ablation is associated with a decrease in all-cause mortality (RR = 0.69; 95% CI, 0.54-0.88; P = .003) and a reduction in hospitalization (RR = 0.62; 95% CI, 0.47-0.82; P = .0006); younger (< 65 years) and male patients derive greater benefit.^6,17 Indications for ablation in patients with heart failure are similar to those in patients without heart failure; ablation can therefore be considered for select heart failure patients who remain symptomatic or for whom AAD has failed.³

Older patients. Ablation can be considered for patients > 75 years with symptomatic paroxysmal AF refractory to AAD or who are intolerant of AAD.³ A study that assessed the benefit of catheter ablation reviewed 587 older (> 75 years) patients with AF, of whom 324 were eligible for ablation. Endpoints were maintenance of sinus rhythm, stroke, death, and major bleeding. Return to normal sinus rhythm was an independent factor, associated with a decrease in the risk of mortality among all patient groups that underwent ablation (HR = 0.36; 95% CI, 0.2-0.63; P = .0005). Age > 75 years (HR = 1.09; 95% CI, 1.01-1.16; P > .02) and depressed ejection fraction < 40% (HR = 2.38; 95% CI, 1.28-4.4; P = .006) were determined to be unfavorable parameters for survival.¹⁸

Complications and risks

Complications of catheter ablation for AF, although infrequent, can be severe (TABLE 3³). Early mortality, defined as death during initial admission or 30-day readmission, occurs in approximately 0.5% of cases; half of deaths take place during readmission.¹¹

Continue to: Complications vary...

Complications vary, based on the type and site of ablation.^19,20 Cardiac tamponade or perforation, the most life-threatening complications, taken together occur in an estimated 1.9% of patients (odds ratio [OR] = 2.98; 95% CI, 1.36-6.56; P = .007).¹¹ Other in-hospital complications independently predictive of death include any cardiac complications (OR = 12.8; 95% CI, 6.86 to 23.8; P < .001) and neurologic complications (cerebrovascular accident and transient ischemic attack) (OR = 8.72; 95% CI, 2.71-28.1; P < .001).

Other complications that do not cause death but might prolong the hospital stay include pericarditis without effusion, anesthesia-related complications, and vascular-access complications. Patients whose ablation is performed at an institution where the volume of ablations is low are also at higher risk of early mortality (OR = 2.35; 95% CI, 1.33-4.15; P = .003).¹⁶

Recurrence is common (TABLE 2^11-13). Risk of recurrence following ablation is significant; early (within 3 months after ablation) recurrence is seen in 50% of patients.^21,22 However, this is a so-called "blanking period"—ie, a temporary period of inflammatory and proarrhythmic changes that are not predictors of later recurrence. The 5-year post-ablation recurrence rate is approximately 25.5%; longstanding persistent and persistent AF and the presence of comorbidities are major risk factors for recurrence.^13,23

Recurrence is also associated with the type of procedure; pulmonary vein isolation, alone or in combination with another type of procedure, results in higher long-term success.^21,23

Other variables affect outcome (TABLE 2^11-13). Following AF ablation, patients with nonparoxysmal AF at baseline, advanced age, sleep apnea and obesity, left atrial enlargement, and any structural heart disease tend to have a poorer long-term (5-year) outcome (ie, freedom from extended episodes of AF).^3,13,23,24

Patients who undergo repeat procedures have higher arrhythmia-free survival; the highest ablation success rate is for patients with paroxysmal AF.^13,23

Exposure to ionizing radiation. Fluoroscopy is required for multiple components of atrial mapping and ablation during RF ablation, including navigation, visualization, and monitoring of catheter placement. Patients undergoing this particular procedure therefore receive significant exposure to ionizing radiation. A reduction in, even complete elimination of, fluoroscopy has been achieved with:

• nonfluoroscopic 3-dimensional mapping systems²⁵
• intracardiac echocardiography, which utilizes ultrasonographic imaging as the primary visual mode for tracking and manipulating the catheter
• robotic guided navigation.^26-28

Continue to: CASE

CASE

At his return visit, Mr. Z says that he is concerned about, first, undergoing catheter ablation at his age and, second, the risks associated with the procedure. You explain that it is true that ablation is ideal in younger patients who have minimal comorbidities and that the risk of complications increases with age—but that there is no cutoff or absolute age contraindication to ablation.

You tell Mr. Z that you will work with him on risk-factor modification in anticipation of ablation. You also assure him that the decision whether to ablate must be a joint one—between him and a cardiologist experienced both in electrophysiology and in performing this highly technical procedure. And you explain that a highly practiced specialist can identify Mr. Z’s risk factors that might make ablation more difficult to perform and affect the long-term outcome.

With Mr. Z’s agreement, you screen for sleep apnea and start him on a lifestyle modification plan to achieve a more ideal weight, explaining that the risk of recurrence of AF after catheter ablation is increased by obesity and sleep apnea, in addition to age. You explain that, based on his CHA₂DS₂–VASc (congestive heart failure; hypertension; age, ≥ 75 years; diabetes; prior stroke, transient ischemic attack, or thromboembolism; vascular disease; age, 65 to 74 years; sex category) score of 3, he will remain on anticoagulation whether or not he has the ablation.

You refer the patient to the nearest high-volume cardiac ablation center.

Last, you caution Mr. Z that, based on his lipid levels, his 10-year risk of heart disease or stroke is elevated. You recommend treatment with a statin agent while he continues his other medications.

Delivering energy to myocardium

Myocardial tissue in pulmonary veins is responsible for most ectopic electrical impulses in patients with drug-refractory AF. The goal of catheter ablation in AF is destruction (scarring) of tissue that is the source of abnormal vein potentials.¹⁵

How RF ablation works. Ablation is most commonly performed using RF energy, a high-frequency form of electrical energy. Electrophysiology studies are carried out at the time of ablation by percutaneous, fluoroscopically guided insertion of 2 to 5 catheters, usually through the femoral or internal jugular vein, which are then positioned within several areas of the heart—usually, the right atrium, bundle of His, right ventricle, and coronary sinus.

Continue to: Electrical current...

Successful ablation is defined as freedom from symptomatic or asymptomatic AF episodes, and depends on AF type; duration and degree of symptoms; and age, sex, and comorbidities.

Electrical current is applied through the catheters from an external generator to stimulate the myocardium and thus determine its electrophysiologic properties. The anatomic and electrical activity of the left atrium and pulmonary veins is then identified, a technique known as electro-anatomical mapping (FIGURE). After arrhythmogenic myocardial tissue is mapped, ablation is carried out with RF energy through the catheter to the pathogenic myocardium from which arrhythmias are initiated or conducted. The result is thermal destruction of tissue and creation of small, shallow lesions that vary in size with the type of catheter and the force of contact pressure applied.^3,29

Other energy sources used in catheter ablation include cryothermal energy, which utilizes liquid nitrous oxide under pressure through a cryocatheter or cryoballoon catheter. Application of cryothermal energy freezes tissue and disrupts cell membranes and any electrical activity. Cryoballoon ablation has been shown to be similarly safe and efficacious as RF ablation in patients with paroxysmal AF.^30,31

Newer laser-based balloon ablations are performed under ultrasonographic guidance and utilize arcs of laser energy delivered to the pathogenic myocardium.³

Thromboembolism prophylaxis

Oral anticoagulation to decrease the risk of stroke is initiated in all patients with AF, based on a thromboembolic risk profile determined by their CHA₂DS₂–VASc score, with anticoagulation recommended when the score is ≥ 2 in men and ≥ 3 in women. Options for anticoagulation include warfarin and one of the novel oral anticoagulants dabigatran, apixaban, rivaroxaban, and edoxaban.⁴ Recommendations are as follows³:

• For patients with a CHA₂DS₂–VASc score of ≥ 2 (men) or ≥ 3 (women), anticoagulation should be continued indefinitely, regardless of how successful the ablation procedure is.
• When patients choose to discontinue anticoagulation, they should be counseled in detail about the risk of doing so. The continued need for frequent arrhythmia monitoring should be emphasized.

The route from primary careto catheter ablation

Perform a thorough evaluation. Patients who present to you with palpitations should first undergo a routine workup for AF, followed by confirmation of the diagnosis. Exclude structural heart disease with echocardiography. Undertake monitoring, which is essential to determine whether symptoms are a reflection of the arrhythmia, using noncontinuous or continuous electrocardiographic (EKG) monitoring. Noncontinuous detection devices include:

• scheduled or symptom-initiated EKG
• a Holter monitor, worn for at least 24 hours and as long as 7 days
• trans-telephonic recordings and patient- or automatically activated devices
• an external loop recorder.³²

Continuous EKG monitoring is more permanent (≥ 12 months). This is usually achieved through an implantable loop powered by a battery that lasts as long as 3 years.³

Ablation: Yes or no? Ablation is not recommended to avoid anticoagulation or when anticoagulation is contraindicated.⁵ With regard to specific patient criteria, the ideal patient:

• is symptomatic
• has failed AAD therapy
• does not have pulmonary disease
• has a normal or mildly dilated left atrium or normal or mildly reduced left ventricular ejection fraction.⁵

Continue to: There is no absolute age...

There is no absolute age or comorbidity contraindication to ablation. The patient should be referred to a cardiologist who has received appropriate training in electrophysiology, to identify comorbidities that (1) increase the technical difficulty of the procedure and baseline risk and (2) affect long-term outcome,¹² and who performs the procedure in a center that has considerable experience with catheter ablation.³³

Once the decision is made to perform ablation, you can provide strategies that optimize the outcome (freedom from AF episodes). Those tactics include weight loss and screening evaluation and, if indicated, treatment for sleep apnea.³

Protocol. Prior to the procedure, the patient fasts overnight; they might be asked to taper or discontinue cardiac medications that have electrophysiologic effects. Studies suggest a low risk of bleeding associated with catheter ablation; anticoagulation should therefore continue uninterrupted for patients undergoing catheter ablation for AF^3,4,34,35; however, this practice varies with the cardiologist or electrophysiologist performing ablation.

Patients whose ablation is performed at an institution where the volume of such procedures is low are at higher risk of early mortality.

Because of the length and complexity of the procedure, electro-anatomical mapping and ablation are conducted with the patient under general anesthesia.³ The patient is kept supine, and remains so for 2 to 4 hours afterward to allow for hemostasis at puncture sites.³

Patients might be monitored overnight, although same-day catheter ablation has been shown to be safe and cost-effective in select patients.^36,37 Post ablation, patients follow up with the cardiologist and electrophysiologist. Long-term arrhythmia monitoring is required.³ Anticoagulation is continued for at least 2 months, and is discontinued based on the patient’s risk for stroke, utilizing their CHA₂DS₂–VASc score.^3,4

CASE

At Mr. Z’s 6-month primary care follow-up, he confirms what has been reported to you as the referring physician: He had a successful catheter ablation and continues to have regular follow-up monitoring with the cardiologist. He is no longer taking amiodarone.

At this visit, he reports no recurrence of AF-associated symptoms or detectable AF on cardiac monitoring. He has lost 8 lbs. You counsel to him to continue to maintain a healthy lifestyle.

CORRESPONDENCE
Amimi S. Osayande MD, FAAFP, Northside-Gwinnett Family Medicine Residency Program, Strickland Family Medicine Center, 665 Duluth Highway, Suite 501, Lawrenceville, GA 30046; [email protected]

CASE

Jack Z, a 75-year-old man with well-controlled hypertension, diabetes controlled by diet, and atrial fibrillation (AF) presents to the family medicine clinic to establish care with you after moving to the community from out of town.

The patient describes a 1-year history of AF. He provides you with an echocardiography report from 6 months ago that shows no evidence of structural heart disease. He takes lisinopril, to control blood pressure; an anticoagulant; a beta-blocker; and amiodarone for rhythm control. Initially, he took flecainide, which was ineffective for rhythm control, before being switched to amiodarone. He had 2 cardioversion procedures, each time after episodes of symptoms. He does not smoke or drink alcohol.

Mr. Z describes worsening palpitations and shortness of breath over the past 9 months. Symptoms now include episodes of exertional fatigue, even when he is not having palpitations. Prior to the episodes of worsening symptoms, he tells you that he lived a “fairly active” life, golfing twice a week.

The patient’s previous primary care physician had encouraged him to talk to his cardiologist about “other options” for managing AF, because levels of his liver enzymes had started to rise (a known adverse effect of amiodarone¹) when measured 3 months ago. He did not undertake that conversation, but asks you now about other treatments for AF.

Atrial fibrillation is the most common sustained cardiac arrhythmia, characterized by discordant electrical activation of the atria due to structural or electrophysiological abnormalities, or both. The disorder is associated with an increased rate of stroke and heart failure and is independently associated with a 1.5- to 2-fold risk of all-cause mortality.²

In this article, we review the pathophysiology of AF; management, including the role of, and indications for, catheter ablation; and patient- and disease-related factors associated with ablation (including odds of success, complications, risk of recurrence, and continuing need for thromboprophylaxis) that family physicians should consider when contemplating referral to a cardiologist or electrophysiologist for catheter ablation for AF.

What provokes AF?

AF is thought to occur as a result of an interaction among 3 phenomena:

• enhanced automaticity of abnormal atrial tissue
• triggered activity of ectopic foci within 1 or more pulmonary veins, lying within the left atrium
• re-entry, in which there is propagation of electrical impulses from an ectopic beat through another pathway.

Continue to: In patients who progress...

In patients who progress from paroxysmal to persistent AF (see “Subtypes,” below), 2 distinct pathways, facilitated by the presence of abnormal tissue, continuously activate one another, thus maintaining the arrhythmia. Myocardial tissue in the pulmonary veins is responsible for most ectopic electrical impulses in patients with drug-refractory AF (see “Rhythm control”).

Subtypes. For the purpose of planning treatment, AF is classified as:

• Paroxysmal. Terminates spontaneously or with intervention ≤ 7 days after onset.
• Persistent. Continuous and sustained for > 7 days.
• Longstanding persistent. Continuous for > 12 months.
• Permanent. The patient and physician accept that there will be no further attempt to restore or maintain sinus rhythm.

Goals of treatment

Primary management goals in patients with AF are 2-fold: control of symptoms and prevention of thromboembolism. A patient with new-onset AF who presents acutely with inadequate rate control and hemodynamic compromise requires urgent assessment to determine the cause of the arrhythmia and need for cardioversion.³ A symptomatic patient with AF who does not have high-risk features (eg, valvular heart disease, mechanical valves) might be a candidate for rhythm control in addition to rate control.^3,4

Rate control. After evaluation in the hospital, a patient who has a rapid ventricular response but remains hemodynamically stable, without evidence of heart failure, should be initiated on a rate-controlling medication, such as a beta-blocker or nondihydropyridine calcium-channel blocker. A resting heart rate goal of < 80 beats per minute (bpm) is recommended for a symptomatic patient with AF. The heart rate goal can be relaxed, to < 110 bpm, in an asymptomatic patient with preserved left ventricular function.^5,6

Rhythm control, indicated in patients who remain symptomatic on rate-controlling medication, can be achieved either with an antiarrhythmic drug (AAD) or by catheter ablation.^4,5 In stable patients, rhythm control should be considered only after a thorough work-up for a reversible cause of AF, and can be achieved with an oral AAD or, in select patients, through catheter ablation (TABLE 1^3,6). Other indications for chronic rhythm control include treatment of patients with ­tachycardia-induced cardiomyopathy.⁵

Continuing symptoms when taking rate-controlling medication for atrial fibrillation is one indication for rhythm control with an antiarrhythmic drug or by catheter ablation.

A major study that documented the benefit of early rhythm control evaluated long-term outcomes in 2789 patients with AF who were undergoing catheter ablation.⁷ Patients were randomized to early rhythm control (catheter ablation or AAD) or “usual care”—ie, in this study, rhythm control limited to symptomatic patients. Primary outcomes were death from cardiovascular causes, stroke, and hospitalization with worsening heart failure or acute coronary syndrome. A first primary outcome event occurred in 249 patients (3.9/100 person-years) assigned to early rhythm control, compared to 316 (5.0 per 100 person-years) in the group assigned to usual care.

The study was terminated early (after 5.1 years) because of overwhelming evidence of efficacy (number need to treat = 7). Although early rhythm control was obtained through both catheter ablation and AAD (hazard ratio [HR] = 0.79; 96% CI, 0.66-0.94; P = .005), success was attributed to the use of catheter ablation for a rhythm-control strategy and its use among patients whose AF was present for < 1 year. Most patients in both treatment groups continued to receive anticoagulation, rate control, and optimization of cardiovascular risk.⁷

Continue to: Notably, direct studies...

Notably, direct studies comparing ablation and AAD have not confirmed the benefit of ablation over AAD in outcomes of all-cause mortality, bleeding, stroke, or cardiac arrest over a 5-year period.⁸

Adverse effects and mortality outcomes with AAD. Concern over using AAD for rhythm control is based mostly on adverse effects and long-term (1-year) mortality outcomes. Long-term AAD therapy has been shown to decrease the recurrence of AF—but without evidence to suggest other mortality benefits.

A meta-analysis of 59 randomized controlled trials reviewed 20,981 patients receiving AAD (including quinidine, disopyramide, propafenone, flecainide, metoprolol, amiodarone, dofetilide, dronedarone, and sotalol) for long-term effects on death, stroke, adverse reactions, and recurrence of AF.⁹ Findings at 10 months suggest that:

• Compared to placebo, amiodarone and sotalol increased the risk of all-cause mortality during the study period.
• There was minimal difference in mortality among patients taking dofetilide or dronedarone, compared to placebo.
• There were insufficient data to draw conclusions about the effect of disopyramide, flecainide, and propafenone on mortality.

Before starting a patient on AAD, the risk of arrhythmias and the potential for these agents to cause toxicity and adverse events should always be discussed.

CASE

You tell Mr. Z that you need to know the status of his comorbidities to make a recommendation about “other” management options, and proceed to take a detailed history.

Recent history. Mr. Z reveals that “today is a good day”: He has had “only 1” episode of palpitations, which resolved on its own. The previous episode, he explains, was 3 days ago, when palpitations were associated with lightheadedness and shortness of breath. He denies chest pains or swelling of the legs.

Physical exam. The patient appears spry, comfortable, and in no acute distress. Vital signs are within normal limits. A body mass index of 28.4 puts him in the “overweight” category. His blood pressure is 118/75 mm Hg.

Continue to: Cardiac examination...

Cardiac examination is significant for an irregular rhythm without murmurs, rubs, or gallops. His lungs are clear bilaterally; his abdomen is soft and nondistended. His extremities show no edema.

Testing. You obtain an electrocardiogram, which demonstrates a controlled ventricular rate of 88 bpm and AF. You order a complete blood count, comprehensive metabolic panel, tests of hemoglobin A1C and thyroid-stimulating hormone, lipid panel, echocardiogram, and a chest radiograph.

Results. The chest radiograph is negative for an acute cardiopulmonary process; cardiac size is normal. Aspartate aminotransferase and alanine aminotransferase levels are higher than twice the normal limit. The echocardiogram reveals an estimated left ventricular ejection fraction of 55% to 60%; no structural abnormalities are noted.

In which AF patients is catheter ablation indicated?

Ablation is recommended for select patients (TABLE 1^3,6) with symptomatic paroxysmal AF that is refractory to AAD or who are intolerant of AAD.^3,6 It is a reasonable first-line therapy for high-performing athletes in whom AAD would affect athletic performance.^3,10 It is also a reasonable option in select patients > 75 years and as an alternative to AAD therapy.³ Finally, catheter ablation should be considered in symptomatic patients with longstanding persistent AF and congestive heart failure, with or without reduced left ventricular ejection fraction.³

CASE

You inform Mr. Z that his symptoms are likely a result of symptomatic paroxysmal AF, which was refractory to flecainide and amiodarone, and that his abnormal liver function test results preclude continued use of amiodarone. You propose Holter monitoring to correlate timing of symptoms with the arrhythmia, but he reports this has been done, and the correlation confirmed, by his previous physician.

You explain that, because the diagnosis of symptomatic paroxysmal AF refractory to AADs has been confirmed, he is categorized as a patient who might benefit from catheter ablation, based on:

• the type of AF (ie, paroxysmal AF is associated with better ablation outcomes)
• persistent symptoms that are refractory to AADs
• his intolerance of AAD
• the length of time since onset of symptoms.

Mr. Z agrees to consider your recommendation.

Continue to: What are the benefits of catheter ablation?

Ablation can be achieved through radiofrequency (RF) ablation, cryoablation, or newer, laser-based balloon ablation. Primary outcomes used to determine the success of any options for performing ablation include mortality, stroke, and hospitalization. Other endpoints include maintenance of sinus rhythm, freedom from AF, reduction in AF burden (estimated through patients’ report of symptoms, recurrence rate, need for a second ablation procedure, and serial long-term monitoring through an implantable cardiac monitoring device), quality of life, and prevention of AF progression.³

Patient and disease variables (TABLE 2^11-13). The success rate of catheter ablation, defined as freedom from either symptomatic or asymptomatic episodes of AF, is dependent on several factors,^3,14 including:

• type of AF (paroxysmal or persistent)
• duration and degree of symptoms
• age
• sex
• comorbidities, including heart failure and structural heart or lung disease.

Overall, in patients with paroxysmal AF, an estimated 75% are symptom free 1 year after ablation.¹⁵ Patients with persistent and longstanding persistent AF experience a lower success rate.

Ablation is recommended in patients with symptomatic paroxysmal atrial fibrillation that is refractory to antiarrhythmics or when they are intolerant of these drugs.

RF catheter ablation has demonstrated superiority to AAD in reducing the need for cardioversion (relative risk [RR] = 0.62; 95% CI, 0.47-0.82) and cardiac-related hospitalization (RR = 0.27; 95% CI, 0.10-0.72;) at 12 months in patients with nonparoxysmal AF (persistent or longstanding persistent).¹⁶

Effect on mortality. Among patients with heart failure with reduced ejection fraction, long-term studies of cardiovascular outcomes 5 years post ablation concluded that ablation is associated with a decrease in all-cause mortality (RR = 0.69; 95% CI, 0.54-0.88; P = .003) and a reduction in hospitalization (RR = 0.62; 95% CI, 0.47-0.82; P = .0006); younger (< 65 years) and male patients derive greater benefit.^6,17 Indications for ablation in patients with heart failure are similar to those in patients without heart failure; ablation can therefore be considered for select heart failure patients who remain symptomatic or for whom AAD has failed.³

Older patients. Ablation can be considered for patients > 75 years with symptomatic paroxysmal AF refractory to AAD or who are intolerant of AAD.³ A study that assessed the benefit of catheter ablation reviewed 587 older (> 75 years) patients with AF, of whom 324 were eligible for ablation. Endpoints were maintenance of sinus rhythm, stroke, death, and major bleeding. Return to normal sinus rhythm was an independent factor, associated with a decrease in the risk of mortality among all patient groups that underwent ablation (HR = 0.36; 95% CI, 0.2-0.63; P = .0005). Age > 75 years (HR = 1.09; 95% CI, 1.01-1.16; P > .02) and depressed ejection fraction < 40% (HR = 2.38; 95% CI, 1.28-4.4; P = .006) were determined to be unfavorable parameters for survival.¹⁸

Complications and risks

Complications of catheter ablation for AF, although infrequent, can be severe (TABLE 3³). Early mortality, defined as death during initial admission or 30-day readmission, occurs in approximately 0.5% of cases; half of deaths take place during readmission.¹¹

Continue to: Complications vary...

Complications vary, based on the type and site of ablation.^19,20 Cardiac tamponade or perforation, the most life-threatening complications, taken together occur in an estimated 1.9% of patients (odds ratio [OR] = 2.98; 95% CI, 1.36-6.56; P = .007).¹¹ Other in-hospital complications independently predictive of death include any cardiac complications (OR = 12.8; 95% CI, 6.86 to 23.8; P < .001) and neurologic complications (cerebrovascular accident and transient ischemic attack) (OR = 8.72; 95% CI, 2.71-28.1; P < .001).

Other complications that do not cause death but might prolong the hospital stay include pericarditis without effusion, anesthesia-related complications, and vascular-access complications. Patients whose ablation is performed at an institution where the volume of ablations is low are also at higher risk of early mortality (OR = 2.35; 95% CI, 1.33-4.15; P = .003).¹⁶

Recurrence is common (TABLE 2^11-13). Risk of recurrence following ablation is significant; early (within 3 months after ablation) recurrence is seen in 50% of patients.^21,22 However, this is a so-called "blanking period"—ie, a temporary period of inflammatory and proarrhythmic changes that are not predictors of later recurrence. The 5-year post-ablation recurrence rate is approximately 25.5%; longstanding persistent and persistent AF and the presence of comorbidities are major risk factors for recurrence.^13,23

Recurrence is also associated with the type of procedure; pulmonary vein isolation, alone or in combination with another type of procedure, results in higher long-term success.^21,23

Other variables affect outcome (TABLE 2^11-13). Following AF ablation, patients with nonparoxysmal AF at baseline, advanced age, sleep apnea and obesity, left atrial enlargement, and any structural heart disease tend to have a poorer long-term (5-year) outcome (ie, freedom from extended episodes of AF).^3,13,23,24

Patients who undergo repeat procedures have higher arrhythmia-free survival; the highest ablation success rate is for patients with paroxysmal AF.^13,23

Exposure to ionizing radiation. Fluoroscopy is required for multiple components of atrial mapping and ablation during RF ablation, including navigation, visualization, and monitoring of catheter placement. Patients undergoing this particular procedure therefore receive significant exposure to ionizing radiation. A reduction in, even complete elimination of, fluoroscopy has been achieved with:

• nonfluoroscopic 3-dimensional mapping systems²⁵
• intracardiac echocardiography, which utilizes ultrasonographic imaging as the primary visual mode for tracking and manipulating the catheter
• robotic guided navigation.^26-28

Continue to: CASE

CASE

At his return visit, Mr. Z says that he is concerned about, first, undergoing catheter ablation at his age and, second, the risks associated with the procedure. You explain that it is true that ablation is ideal in younger patients who have minimal comorbidities and that the risk of complications increases with age—but that there is no cutoff or absolute age contraindication to ablation.

You tell Mr. Z that you will work with him on risk-factor modification in anticipation of ablation. You also assure him that the decision whether to ablate must be a joint one—between him and a cardiologist experienced both in electrophysiology and in performing this highly technical procedure. And you explain that a highly practiced specialist can identify Mr. Z’s risk factors that might make ablation more difficult to perform and affect the long-term outcome.

With Mr. Z’s agreement, you screen for sleep apnea and start him on a lifestyle modification plan to achieve a more ideal weight, explaining that the risk of recurrence of AF after catheter ablation is increased by obesity and sleep apnea, in addition to age. You explain that, based on his CHA₂DS₂–VASc (congestive heart failure; hypertension; age, ≥ 75 years; diabetes; prior stroke, transient ischemic attack, or thromboembolism; vascular disease; age, 65 to 74 years; sex category) score of 3, he will remain on anticoagulation whether or not he has the ablation.

You refer the patient to the nearest high-volume cardiac ablation center.

Last, you caution Mr. Z that, based on his lipid levels, his 10-year risk of heart disease or stroke is elevated. You recommend treatment with a statin agent while he continues his other medications.

Delivering energy to myocardium

Myocardial tissue in pulmonary veins is responsible for most ectopic electrical impulses in patients with drug-refractory AF. The goal of catheter ablation in AF is destruction (scarring) of tissue that is the source of abnormal vein potentials.¹⁵

How RF ablation works. Ablation is most commonly performed using RF energy, a high-frequency form of electrical energy. Electrophysiology studies are carried out at the time of ablation by percutaneous, fluoroscopically guided insertion of 2 to 5 catheters, usually through the femoral or internal jugular vein, which are then positioned within several areas of the heart—usually, the right atrium, bundle of His, right ventricle, and coronary sinus.

Continue to: Electrical current...

Successful ablation is defined as freedom from symptomatic or asymptomatic AF episodes, and depends on AF type; duration and degree of symptoms; and age, sex, and comorbidities.

Electrical current is applied through the catheters from an external generator to stimulate the myocardium and thus determine its electrophysiologic properties. The anatomic and electrical activity of the left atrium and pulmonary veins is then identified, a technique known as electro-anatomical mapping (FIGURE). After arrhythmogenic myocardial tissue is mapped, ablation is carried out with RF energy through the catheter to the pathogenic myocardium from which arrhythmias are initiated or conducted. The result is thermal destruction of tissue and creation of small, shallow lesions that vary in size with the type of catheter and the force of contact pressure applied.^3,29

Other energy sources used in catheter ablation include cryothermal energy, which utilizes liquid nitrous oxide under pressure through a cryocatheter or cryoballoon catheter. Application of cryothermal energy freezes tissue and disrupts cell membranes and any electrical activity. Cryoballoon ablation has been shown to be similarly safe and efficacious as RF ablation in patients with paroxysmal AF.^30,31

Newer laser-based balloon ablations are performed under ultrasonographic guidance and utilize arcs of laser energy delivered to the pathogenic myocardium.³

Thromboembolism prophylaxis

Oral anticoagulation to decrease the risk of stroke is initiated in all patients with AF, based on a thromboembolic risk profile determined by their CHA₂DS₂–VASc score, with anticoagulation recommended when the score is ≥ 2 in men and ≥ 3 in women. Options for anticoagulation include warfarin and one of the novel oral anticoagulants dabigatran, apixaban, rivaroxaban, and edoxaban.⁴ Recommendations are as follows³:

• For patients with a CHA₂DS₂–VASc score of ≥ 2 (men) or ≥ 3 (women), anticoagulation should be continued indefinitely, regardless of how successful the ablation procedure is.
• When patients choose to discontinue anticoagulation, they should be counseled in detail about the risk of doing so. The continued need for frequent arrhythmia monitoring should be emphasized.

The route from primary careto catheter ablation

Perform a thorough evaluation. Patients who present to you with palpitations should first undergo a routine workup for AF, followed by confirmation of the diagnosis. Exclude structural heart disease with echocardiography. Undertake monitoring, which is essential to determine whether symptoms are a reflection of the arrhythmia, using noncontinuous or continuous electrocardiographic (EKG) monitoring. Noncontinuous detection devices include:

• scheduled or symptom-initiated EKG
• a Holter monitor, worn for at least 24 hours and as long as 7 days
• trans-telephonic recordings and patient- or automatically activated devices
• an external loop recorder.³²

Continuous EKG monitoring is more permanent (≥ 12 months). This is usually achieved through an implantable loop powered by a battery that lasts as long as 3 years.³

Ablation: Yes or no? Ablation is not recommended to avoid anticoagulation or when anticoagulation is contraindicated.⁵ With regard to specific patient criteria, the ideal patient:

• is symptomatic
• has failed AAD therapy
• does not have pulmonary disease
• has a normal or mildly dilated left atrium or normal or mildly reduced left ventricular ejection fraction.⁵

Continue to: There is no absolute age...

There is no absolute age or comorbidity contraindication to ablation. The patient should be referred to a cardiologist who has received appropriate training in electrophysiology, to identify comorbidities that (1) increase the technical difficulty of the procedure and baseline risk and (2) affect long-term outcome,¹² and who performs the procedure in a center that has considerable experience with catheter ablation.³³

Once the decision is made to perform ablation, you can provide strategies that optimize the outcome (freedom from AF episodes). Those tactics include weight loss and screening evaluation and, if indicated, treatment for sleep apnea.³

Protocol. Prior to the procedure, the patient fasts overnight; they might be asked to taper or discontinue cardiac medications that have electrophysiologic effects. Studies suggest a low risk of bleeding associated with catheter ablation; anticoagulation should therefore continue uninterrupted for patients undergoing catheter ablation for AF^3,4,34,35; however, this practice varies with the cardiologist or electrophysiologist performing ablation.

Patients whose ablation is performed at an institution where the volume of such procedures is low are at higher risk of early mortality.

Because of the length and complexity of the procedure, electro-anatomical mapping and ablation are conducted with the patient under general anesthesia.³ The patient is kept supine, and remains so for 2 to 4 hours afterward to allow for hemostasis at puncture sites.³

Patients might be monitored overnight, although same-day catheter ablation has been shown to be safe and cost-effective in select patients.^36,37 Post ablation, patients follow up with the cardiologist and electrophysiologist. Long-term arrhythmia monitoring is required.³ Anticoagulation is continued for at least 2 months, and is discontinued based on the patient’s risk for stroke, utilizing their CHA₂DS₂–VASc score.^3,4

CASE

At Mr. Z’s 6-month primary care follow-up, he confirms what has been reported to you as the referring physician: He had a successful catheter ablation and continues to have regular follow-up monitoring with the cardiologist. He is no longer taking amiodarone.

At this visit, he reports no recurrence of AF-associated symptoms or detectable AF on cardiac monitoring. He has lost 8 lbs. You counsel to him to continue to maintain a healthy lifestyle.

CORRESPONDENCE
Amimi S. Osayande MD, FAAFP, Northside-Gwinnett Family Medicine Residency Program, Strickland Family Medicine Center, 665 Duluth Highway, Suite 501, Lawrenceville, GA 30046; [email protected]

The Diagnosis: Cystic Neutrophilic Granulomatous Mastitis

The histopathologic findings in our patient were characteristic of cystic neutrophilic granulomatous mastitis (CNGM), a rare granulomatous mastitis associated with Corynebacterium and suppurative lipogranulomas. Although not seen in our patient, the lipid vacuoles may contain gram-positive bacilli.¹ The surrounding mixed inflammatory infiltrate contains Langerhans giant cells, lymphocytes, and neutrophils. Cystic neutrophilic granulomatous mastitis is seen in parous women of reproductive age. Physical examination demonstrates a palpable painful mass on the breast. Wound cultures frequently are negative, likely due to difficulty culturing Corynebacterium and prophylactic antibiotic treatment. Given the association with Corynebacterium species, early diagnosis of CNGM is essential in offering patients the most appropriate treatment. Prolonged antibiotic therapy specifically directed to corynebacteria is required, sometimes even beyond resolution of clinical symptoms. The diagnosis of CNGM often is missed or delayed due to its rarity and many potential mimickers. Clinically, CNGM may be virtually impossible to discern from invasive carcinoma.¹

Our patient was treated with vancomycin and cefepime with incision and drainage as an inpatient. Upon discharge, she was started on prednisone 1 mg/kg daily tapered by 10 mg every 5 days over 1 month and doxycycline 100 mg twice daily. She was then transitioned to topical hydrocortisone and bacitracin; she reported decreased swelling and pain. No new lesions formed after the initiation of therapy; however, most lesions remained open. Cystic neutrophilic granulomatous mastitis remains a challenging entity to treat, with a variable response rate reported in the literature for antibiotics such as doxycycline and systemic and topical steroids as well as immunosuppressants including methotrexate.^2,3

Cystic neutrophilic granulomatous mastitis can be distinguished from hidradenitis suppurativa clinically because ulcerating lesions can involve the superior portions of the breast in CNGM, whereas hidradenitis suppurativa typically is restricted to the lower intertriginous parts of the breast. Other mimics of CNGM can be distinguished with biopsy. Histology of pyoderma gangrenosum lacks prominent granuloma formation. Although sarcoidosis and mycobacterial infection show prominent granulomas, neither show the characteristic lipogranulomas seen in CNGM. Additionally, the granulomas of sarcoidosis are much larger and deeper than CNGM. Mycobacterial granulomas also typically reveal bacilli with acid-fast bacilli staining or via wound culture.

The Diagnosis: Cystic Neutrophilic Granulomatous Mastitis

The histopathologic findings in our patient were characteristic of cystic neutrophilic granulomatous mastitis (CNGM), a rare granulomatous mastitis associated with Corynebacterium and suppurative lipogranulomas. Although not seen in our patient, the lipid vacuoles may contain gram-positive bacilli.¹ The surrounding mixed inflammatory infiltrate contains Langerhans giant cells, lymphocytes, and neutrophils. Cystic neutrophilic granulomatous mastitis is seen in parous women of reproductive age. Physical examination demonstrates a palpable painful mass on the breast. Wound cultures frequently are negative, likely due to difficulty culturing Corynebacterium and prophylactic antibiotic treatment. Given the association with Corynebacterium species, early diagnosis of CNGM is essential in offering patients the most appropriate treatment. Prolonged antibiotic therapy specifically directed to corynebacteria is required, sometimes even beyond resolution of clinical symptoms. The diagnosis of CNGM often is missed or delayed due to its rarity and many potential mimickers. Clinically, CNGM may be virtually impossible to discern from invasive carcinoma.¹

Our patient was treated with vancomycin and cefepime with incision and drainage as an inpatient. Upon discharge, she was started on prednisone 1 mg/kg daily tapered by 10 mg every 5 days over 1 month and doxycycline 100 mg twice daily. She was then transitioned to topical hydrocortisone and bacitracin; she reported decreased swelling and pain. No new lesions formed after the initiation of therapy; however, most lesions remained open. Cystic neutrophilic granulomatous mastitis remains a challenging entity to treat, with a variable response rate reported in the literature for antibiotics such as doxycycline and systemic and topical steroids as well as immunosuppressants including methotrexate.^2,3

Cystic neutrophilic granulomatous mastitis can be distinguished from hidradenitis suppurativa clinically because ulcerating lesions can involve the superior portions of the breast in CNGM, whereas hidradenitis suppurativa typically is restricted to the lower intertriginous parts of the breast. Other mimics of CNGM can be distinguished with biopsy. Histology of pyoderma gangrenosum lacks prominent granuloma formation. Although sarcoidosis and mycobacterial infection show prominent granulomas, neither show the characteristic lipogranulomas seen in CNGM. Additionally, the granulomas of sarcoidosis are much larger and deeper than CNGM. Mycobacterial granulomas also typically reveal bacilli with acid-fast bacilli staining or via wound culture.

The Diagnosis: Cystic Neutrophilic Granulomatous Mastitis

The histopathologic findings in our patient were characteristic of cystic neutrophilic granulomatous mastitis (CNGM), a rare granulomatous mastitis associated with Corynebacterium and suppurative lipogranulomas. Although not seen in our patient, the lipid vacuoles may contain gram-positive bacilli.¹ The surrounding mixed inflammatory infiltrate contains Langerhans giant cells, lymphocytes, and neutrophils. Cystic neutrophilic granulomatous mastitis is seen in parous women of reproductive age. Physical examination demonstrates a palpable painful mass on the breast. Wound cultures frequently are negative, likely due to difficulty culturing Corynebacterium and prophylactic antibiotic treatment. Given the association with Corynebacterium species, early diagnosis of CNGM is essential in offering patients the most appropriate treatment. Prolonged antibiotic therapy specifically directed to corynebacteria is required, sometimes even beyond resolution of clinical symptoms. The diagnosis of CNGM often is missed or delayed due to its rarity and many potential mimickers. Clinically, CNGM may be virtually impossible to discern from invasive carcinoma.¹

Our patient was treated with vancomycin and cefepime with incision and drainage as an inpatient. Upon discharge, she was started on prednisone 1 mg/kg daily tapered by 10 mg every 5 days over 1 month and doxycycline 100 mg twice daily. She was then transitioned to topical hydrocortisone and bacitracin; she reported decreased swelling and pain. No new lesions formed after the initiation of therapy; however, most lesions remained open. Cystic neutrophilic granulomatous mastitis remains a challenging entity to treat, with a variable response rate reported in the literature for antibiotics such as doxycycline and systemic and topical steroids as well as immunosuppressants including methotrexate.^2,3

Cystic neutrophilic granulomatous mastitis can be distinguished from hidradenitis suppurativa clinically because ulcerating lesions can involve the superior portions of the breast in CNGM, whereas hidradenitis suppurativa typically is restricted to the lower intertriginous parts of the breast. Other mimics of CNGM can be distinguished with biopsy. Histology of pyoderma gangrenosum lacks prominent granuloma formation. Although sarcoidosis and mycobacterial infection show prominent granulomas, neither show the characteristic lipogranulomas seen in CNGM. Additionally, the granulomas of sarcoidosis are much larger and deeper than CNGM. Mycobacterial granulomas also typically reveal bacilli with acid-fast bacilli staining or via wound culture.

The Diagnosis: Blastic Plasmacytoid Dendritic Cell Neoplasm

A diagnosis of blastic plasmacytoid dendritic cell neoplasm (BPDCN) was rendered. Subsequent needle core biopsy of a left axillary lymph node as well as bone marrow aspiration and biopsy revealed a similar diffuse blastoid infiltrate with an identical immunophenotype to that in the skin biopsy from the pretibial mass and peripheral blood.

Previously known as blastic natural killer cell leukemia/lymphoma or agranular CD4+/CD56+ hematodermic neoplasm/tumor, BPDCN is a rare, clinically aggressive hematologic malignancy derived from the precursors of plasmacytoid dendritic cells. It often is diagnostically challenging, particularly when presenting at noncutaneous sites and in unusual (young) patient populations.¹ It was included with other myeloid neoplasms in the 2008 World Health Organization classification; however, in the 2017 classification it was categorized as a separate entity. Blastic plasmacytoid dendritic cell neoplasm typically presents in the skin of elderly patients (age range at diagnosis, 61–67 years) with or without bone marrow involvement and systemic dissemination.^1,2 The skin is the most common clinical site of disease in typical cases of BPDCN and often precedes bone marrow involvement. Thus, skin biopsy often is the key to making the diagnosis. Diagnosis of BPDCN may be delayed because of diagnostic pitfalls. Patients usually present with asymptomatic solitary or multiple lesions.^3-5 Blastic plasmacytoid dendritic cell neoplasm can present as an isolated purplish nodule or bruiselike papule or more commonly as disseminated purplish nodules, papules, and macules. Isolated nodules are found on the head and lower limbs and can be more than 10 cm in diameter. Peripheral blood and bone marrow may be minimally involved at presentation but invariably become involved with the progression of disease. Cytopenia can occur at diagnosis and in a minority of severe cases indicates bone marrow failure.^2-6

Skin involvement of BPDCN is thought to be secondary to the expression of skin migration molecules, such as cutaneous lymphocyte-associated antigen, one of the E-selectin ligands, which binds to E-selectin on high endothelial venules. In addition, the local dermal microenvironment of chemokines binding CXCR3, CXCR4, CCR6, or CCR7 present on neoplastic cells possibly leads to skin involvement. The full mechanism underlying the cutaneous tropism is still to be elucidated.^4-7 Infiltration of the oral mucosa is seen in some patients, but it may be underreported. Mucosal disease typically appears similarly to cutaneous disease.

The cutaneous differential diagnosis for BPDCN depends on the clinical presentation, extent of disease spread, and thickness of infiltration. It includes common nonneoplastic diseases such as traumatic ecchymoses; purpuric disorders; extramedullary hematopoiesis; and soft-tissue neoplasms such as angiosarcoma, Kaposi sarcoma, neuroblastoma, and vascular metastases, as well as skin involvement by other hematologic neoplasms. An adequate incisional biopsy rather than a punch or shave biopsy is recommended for diagnosis. Dermatologists should alert the pathologist that BPDCN is in the clinical differential diagnosis when possible so that judicious use of appropriate immunophenotypic markers such as CD123, CD4, CD56, and T-cell leukemia/lymphoma protein 1 will avoid misdiagnosis of this aggressive condition, in addition to excluding acute myeloid leukemia, which also may express 3 of the above markers. However, most cases of acute myeloid leukemia lack terminal deoxynucleotidyl transferase (TdT) and express monocytic and other myeloid markers. Terminal deoxynucleotidyl transferase is positive in approximately one-third of cases of BPDCN, with expression in 10% to 80% of cells.¹

It is important to include BPDCN in the differential diagnosis of immunophenotypically aberrant hematologic tumors. Diffuse large B-cell lymphoma, leg type, accounts for 4% of all primary cutaneous B-cell lymphomas.¹ Compared with BPDCN, diffuse large B-cell lymphoma usually occurs in an older age group and is of B-cell lineage. Morphologically, these neoplasms are composed of a monotonous, diffuse, nonepidermotropic infiltrate of confluent sheets of centroblasts and immunoblasts (Figure 1). They may share immunohistochemical markers of CD79a, multiple myeloma 1, Bcl-2, and Bcl-6; however, they lack plasmacytoid dendritic cell (PDC)– associated antigens such as CD4, CD56, CD123, and T-cell leukemia/lymphoma protein 1.¹

Adult T-cell leukemia/lymphoma is a neoplasm histologically composed of highly pleomorphic medium- to large-sized T cells with an irregular multilobated nuclear contour, so-called flower cells, in the peripheral blood. The nuclear chromatin is coarse and clumped with prominent nucleoli. Blastlike cells with dispersed chromatin are present in variable proportions. Most patients present with widespread lymph node and peripheral blood involvement. Skin is involved in more than half of patients with an epidermal as well as dermal pattern of infiltration (mainly perivascular)(Figure 2). Adult T-cell leukemia/lymphoma is endemic in several regions of the world, and the distribution is closely linked to the prevalence of human T-cell lymphotropic virus type 1 in the population. This neoplasm is of T-cell lineage and may share CD4 but not PDC-associated antigens with BPDCN.¹

Cutaneous involvement by T-cell lymphoblastic leukemia/lymphoma (T-LBL) is a rare occurrence with a frequency of approximately 4.3%.8 T-cell lymphoblastic leukemia/lymphoma usually presents as multiple skin lesions throughout the body. Almost all cutaneous T-LBL cases are seen in association with bone marrow and/or mediastinal, lymph node, or extranodal involvement. Cutaneous T-LBLs present as a diffuse monomorphous infiltrate located in the entire dermis and subcutis without epidermotropism, composed of medium to large blasts with finely dispersed chromatin and relatively prominent nucleoli (Figure 3). Immunophenotyping studies show an immature T-cell immunophenotype, with expression of TdT (usually uniform), CD7, and cytoplasmic CD3 and an absence of PDC-associated antigens.⁸

Primary cutaneous γδ T-cell lymphoma (PCGDTL) is a neoplasm primarily involving the skin. Often rapidly fatal, PCGDTL has a broad clinical spectrum that may include indolent variants—subcutaneous, epidermotropic, and dermal. Patients typically present with nodular lesions that progress to ulceration and necrosis. Early lesions can be confused with erythema nodosum, mycosis fungoides, or infection. Histologically, they show variable epidermotropism as well as dermal and subcutaneous involvement by medium to large cells with coarse clumped chromatin (Figure 4). Large blastic cells with vesicular nuclei and prominent nucleoli are infrequent. In contrast to BPCDN, the neoplastic lymphocytes in dermal and subcutaneous PCGDTL typically are positive for T-cell intracellular antigen-1 and granzyme B with loss of CD4.⁹

At the time of presentation, 27% to 87% of BPDCN patients will have bone marrow involvement, 22% to 28% will have blood involvement, and 6% to 41% will have lymph node involvement.^{1-4,6,7,10,11} The clinical course is aggressive, with a median survival of 10.0 to 19.8 months, irrespective of the initial pattern of disease.¹ Most cases have shown initial response to multiagent chemotherapy, but relapses with subsequent resistance to drugs regularly have been observed. Age has an adverse impact of prognosis. Low TdT expression has been associated with shorter survival.¹ Approximately 10% to 20% of cases of BPDCN are associated with or develop into chronic myelogenous leukemia, myelodysplastic syndrome, or acute myeloid leukemia.^1,4 Pediatric patients have a greater 5-year overall survival rate than older patients, and overall survival worsens with increasing age. The extent of cutaneous involvement and presence of systemic involvement at initial presentation do not seem to be strong predictors of survival.^{1,2,5-7,10-12} In a retrospective analysis of 90 patients, Julia et al¹² found that the type of skin disease did not predict survival. Specifically, the presence of nodular lesions and disseminated skin involvement were not adverse prognostic factors compared with macular lesions limited to 1 or 2 body areas.¹²

The Diagnosis: Blastic Plasmacytoid Dendritic Cell Neoplasm

A diagnosis of blastic plasmacytoid dendritic cell neoplasm (BPDCN) was rendered. Subsequent needle core biopsy of a left axillary lymph node as well as bone marrow aspiration and biopsy revealed a similar diffuse blastoid infiltrate with an identical immunophenotype to that in the skin biopsy from the pretibial mass and peripheral blood.

Previously known as blastic natural killer cell leukemia/lymphoma or agranular CD4+/CD56+ hematodermic neoplasm/tumor, BPDCN is a rare, clinically aggressive hematologic malignancy derived from the precursors of plasmacytoid dendritic cells. It often is diagnostically challenging, particularly when presenting at noncutaneous sites and in unusual (young) patient populations.¹ It was included with other myeloid neoplasms in the 2008 World Health Organization classification; however, in the 2017 classification it was categorized as a separate entity. Blastic plasmacytoid dendritic cell neoplasm typically presents in the skin of elderly patients (age range at diagnosis, 61–67 years) with or without bone marrow involvement and systemic dissemination.^1,2 The skin is the most common clinical site of disease in typical cases of BPDCN and often precedes bone marrow involvement. Thus, skin biopsy often is the key to making the diagnosis. Diagnosis of BPDCN may be delayed because of diagnostic pitfalls. Patients usually present with asymptomatic solitary or multiple lesions.^3-5 Blastic plasmacytoid dendritic cell neoplasm can present as an isolated purplish nodule or bruiselike papule or more commonly as disseminated purplish nodules, papules, and macules. Isolated nodules are found on the head and lower limbs and can be more than 10 cm in diameter. Peripheral blood and bone marrow may be minimally involved at presentation but invariably become involved with the progression of disease. Cytopenia can occur at diagnosis and in a minority of severe cases indicates bone marrow failure.^2-6

Skin involvement of BPDCN is thought to be secondary to the expression of skin migration molecules, such as cutaneous lymphocyte-associated antigen, one of the E-selectin ligands, which binds to E-selectin on high endothelial venules. In addition, the local dermal microenvironment of chemokines binding CXCR3, CXCR4, CCR6, or CCR7 present on neoplastic cells possibly leads to skin involvement. The full mechanism underlying the cutaneous tropism is still to be elucidated.^4-7 Infiltration of the oral mucosa is seen in some patients, but it may be underreported. Mucosal disease typically appears similarly to cutaneous disease.

The cutaneous differential diagnosis for BPDCN depends on the clinical presentation, extent of disease spread, and thickness of infiltration. It includes common nonneoplastic diseases such as traumatic ecchymoses; purpuric disorders; extramedullary hematopoiesis; and soft-tissue neoplasms such as angiosarcoma, Kaposi sarcoma, neuroblastoma, and vascular metastases, as well as skin involvement by other hematologic neoplasms. An adequate incisional biopsy rather than a punch or shave biopsy is recommended for diagnosis. Dermatologists should alert the pathologist that BPDCN is in the clinical differential diagnosis when possible so that judicious use of appropriate immunophenotypic markers such as CD123, CD4, CD56, and T-cell leukemia/lymphoma protein 1 will avoid misdiagnosis of this aggressive condition, in addition to excluding acute myeloid leukemia, which also may express 3 of the above markers. However, most cases of acute myeloid leukemia lack terminal deoxynucleotidyl transferase (TdT) and express monocytic and other myeloid markers. Terminal deoxynucleotidyl transferase is positive in approximately one-third of cases of BPDCN, with expression in 10% to 80% of cells.¹

It is important to include BPDCN in the differential diagnosis of immunophenotypically aberrant hematologic tumors. Diffuse large B-cell lymphoma, leg type, accounts for 4% of all primary cutaneous B-cell lymphomas.¹ Compared with BPDCN, diffuse large B-cell lymphoma usually occurs in an older age group and is of B-cell lineage. Morphologically, these neoplasms are composed of a monotonous, diffuse, nonepidermotropic infiltrate of confluent sheets of centroblasts and immunoblasts (Figure 1). They may share immunohistochemical markers of CD79a, multiple myeloma 1, Bcl-2, and Bcl-6; however, they lack plasmacytoid dendritic cell (PDC)– associated antigens such as CD4, CD56, CD123, and T-cell leukemia/lymphoma protein 1.¹

Adult T-cell leukemia/lymphoma is a neoplasm histologically composed of highly pleomorphic medium- to large-sized T cells with an irregular multilobated nuclear contour, so-called flower cells, in the peripheral blood. The nuclear chromatin is coarse and clumped with prominent nucleoli. Blastlike cells with dispersed chromatin are present in variable proportions. Most patients present with widespread lymph node and peripheral blood involvement. Skin is involved in more than half of patients with an epidermal as well as dermal pattern of infiltration (mainly perivascular)(Figure 2). Adult T-cell leukemia/lymphoma is endemic in several regions of the world, and the distribution is closely linked to the prevalence of human T-cell lymphotropic virus type 1 in the population. This neoplasm is of T-cell lineage and may share CD4 but not PDC-associated antigens with BPDCN.¹

Cutaneous involvement by T-cell lymphoblastic leukemia/lymphoma (T-LBL) is a rare occurrence with a frequency of approximately 4.3%.8 T-cell lymphoblastic leukemia/lymphoma usually presents as multiple skin lesions throughout the body. Almost all cutaneous T-LBL cases are seen in association with bone marrow and/or mediastinal, lymph node, or extranodal involvement. Cutaneous T-LBLs present as a diffuse monomorphous infiltrate located in the entire dermis and subcutis without epidermotropism, composed of medium to large blasts with finely dispersed chromatin and relatively prominent nucleoli (Figure 3). Immunophenotyping studies show an immature T-cell immunophenotype, with expression of TdT (usually uniform), CD7, and cytoplasmic CD3 and an absence of PDC-associated antigens.⁸

Primary cutaneous γδ T-cell lymphoma (PCGDTL) is a neoplasm primarily involving the skin. Often rapidly fatal, PCGDTL has a broad clinical spectrum that may include indolent variants—subcutaneous, epidermotropic, and dermal. Patients typically present with nodular lesions that progress to ulceration and necrosis. Early lesions can be confused with erythema nodosum, mycosis fungoides, or infection. Histologically, they show variable epidermotropism as well as dermal and subcutaneous involvement by medium to large cells with coarse clumped chromatin (Figure 4). Large blastic cells with vesicular nuclei and prominent nucleoli are infrequent. In contrast to BPCDN, the neoplastic lymphocytes in dermal and subcutaneous PCGDTL typically are positive for T-cell intracellular antigen-1 and granzyme B with loss of CD4.⁹

At the time of presentation, 27% to 87% of BPDCN patients will have bone marrow involvement, 22% to 28% will have blood involvement, and 6% to 41% will have lymph node involvement.^{1-4,6,7,10,11} The clinical course is aggressive, with a median survival of 10.0 to 19.8 months, irrespective of the initial pattern of disease.¹ Most cases have shown initial response to multiagent chemotherapy, but relapses with subsequent resistance to drugs regularly have been observed. Age has an adverse impact of prognosis. Low TdT expression has been associated with shorter survival.¹ Approximately 10% to 20% of cases of BPDCN are associated with or develop into chronic myelogenous leukemia, myelodysplastic syndrome, or acute myeloid leukemia.^1,4 Pediatric patients have a greater 5-year overall survival rate than older patients, and overall survival worsens with increasing age. The extent of cutaneous involvement and presence of systemic involvement at initial presentation do not seem to be strong predictors of survival.^{1,2,5-7,10-12} In a retrospective analysis of 90 patients, Julia et al¹² found that the type of skin disease did not predict survival. Specifically, the presence of nodular lesions and disseminated skin involvement were not adverse prognostic factors compared with macular lesions limited to 1 or 2 body areas.¹²

The Diagnosis: Blastic Plasmacytoid Dendritic Cell Neoplasm

A diagnosis of blastic plasmacytoid dendritic cell neoplasm (BPDCN) was rendered. Subsequent needle core biopsy of a left axillary lymph node as well as bone marrow aspiration and biopsy revealed a similar diffuse blastoid infiltrate with an identical immunophenotype to that in the skin biopsy from the pretibial mass and peripheral blood.

Previously known as blastic natural killer cell leukemia/lymphoma or agranular CD4+/CD56+ hematodermic neoplasm/tumor, BPDCN is a rare, clinically aggressive hematologic malignancy derived from the precursors of plasmacytoid dendritic cells. It often is diagnostically challenging, particularly when presenting at noncutaneous sites and in unusual (young) patient populations.¹ It was included with other myeloid neoplasms in the 2008 World Health Organization classification; however, in the 2017 classification it was categorized as a separate entity. Blastic plasmacytoid dendritic cell neoplasm typically presents in the skin of elderly patients (age range at diagnosis, 61–67 years) with or without bone marrow involvement and systemic dissemination.^1,2 The skin is the most common clinical site of disease in typical cases of BPDCN and often precedes bone marrow involvement. Thus, skin biopsy often is the key to making the diagnosis. Diagnosis of BPDCN may be delayed because of diagnostic pitfalls. Patients usually present with asymptomatic solitary or multiple lesions.^3-5 Blastic plasmacytoid dendritic cell neoplasm can present as an isolated purplish nodule or bruiselike papule or more commonly as disseminated purplish nodules, papules, and macules. Isolated nodules are found on the head and lower limbs and can be more than 10 cm in diameter. Peripheral blood and bone marrow may be minimally involved at presentation but invariably become involved with the progression of disease. Cytopenia can occur at diagnosis and in a minority of severe cases indicates bone marrow failure.^2-6

Skin involvement of BPDCN is thought to be secondary to the expression of skin migration molecules, such as cutaneous lymphocyte-associated antigen, one of the E-selectin ligands, which binds to E-selectin on high endothelial venules. In addition, the local dermal microenvironment of chemokines binding CXCR3, CXCR4, CCR6, or CCR7 present on neoplastic cells possibly leads to skin involvement. The full mechanism underlying the cutaneous tropism is still to be elucidated.^4-7 Infiltration of the oral mucosa is seen in some patients, but it may be underreported. Mucosal disease typically appears similarly to cutaneous disease.

The cutaneous differential diagnosis for BPDCN depends on the clinical presentation, extent of disease spread, and thickness of infiltration. It includes common nonneoplastic diseases such as traumatic ecchymoses; purpuric disorders; extramedullary hematopoiesis; and soft-tissue neoplasms such as angiosarcoma, Kaposi sarcoma, neuroblastoma, and vascular metastases, as well as skin involvement by other hematologic neoplasms. An adequate incisional biopsy rather than a punch or shave biopsy is recommended for diagnosis. Dermatologists should alert the pathologist that BPDCN is in the clinical differential diagnosis when possible so that judicious use of appropriate immunophenotypic markers such as CD123, CD4, CD56, and T-cell leukemia/lymphoma protein 1 will avoid misdiagnosis of this aggressive condition, in addition to excluding acute myeloid leukemia, which also may express 3 of the above markers. However, most cases of acute myeloid leukemia lack terminal deoxynucleotidyl transferase (TdT) and express monocytic and other myeloid markers. Terminal deoxynucleotidyl transferase is positive in approximately one-third of cases of BPDCN, with expression in 10% to 80% of cells.¹

It is important to include BPDCN in the differential diagnosis of immunophenotypically aberrant hematologic tumors. Diffuse large B-cell lymphoma, leg type, accounts for 4% of all primary cutaneous B-cell lymphomas.¹ Compared with BPDCN, diffuse large B-cell lymphoma usually occurs in an older age group and is of B-cell lineage. Morphologically, these neoplasms are composed of a monotonous, diffuse, nonepidermotropic infiltrate of confluent sheets of centroblasts and immunoblasts (Figure 1). They may share immunohistochemical markers of CD79a, multiple myeloma 1, Bcl-2, and Bcl-6; however, they lack plasmacytoid dendritic cell (PDC)– associated antigens such as CD4, CD56, CD123, and T-cell leukemia/lymphoma protein 1.¹

Adult T-cell leukemia/lymphoma is a neoplasm histologically composed of highly pleomorphic medium- to large-sized T cells with an irregular multilobated nuclear contour, so-called flower cells, in the peripheral blood. The nuclear chromatin is coarse and clumped with prominent nucleoli. Blastlike cells with dispersed chromatin are present in variable proportions. Most patients present with widespread lymph node and peripheral blood involvement. Skin is involved in more than half of patients with an epidermal as well as dermal pattern of infiltration (mainly perivascular)(Figure 2). Adult T-cell leukemia/lymphoma is endemic in several regions of the world, and the distribution is closely linked to the prevalence of human T-cell lymphotropic virus type 1 in the population. This neoplasm is of T-cell lineage and may share CD4 but not PDC-associated antigens with BPDCN.¹

Cutaneous involvement by T-cell lymphoblastic leukemia/lymphoma (T-LBL) is a rare occurrence with a frequency of approximately 4.3%.8 T-cell lymphoblastic leukemia/lymphoma usually presents as multiple skin lesions throughout the body. Almost all cutaneous T-LBL cases are seen in association with bone marrow and/or mediastinal, lymph node, or extranodal involvement. Cutaneous T-LBLs present as a diffuse monomorphous infiltrate located in the entire dermis and subcutis without epidermotropism, composed of medium to large blasts with finely dispersed chromatin and relatively prominent nucleoli (Figure 3). Immunophenotyping studies show an immature T-cell immunophenotype, with expression of TdT (usually uniform), CD7, and cytoplasmic CD3 and an absence of PDC-associated antigens.⁸

Primary cutaneous γδ T-cell lymphoma (PCGDTL) is a neoplasm primarily involving the skin. Often rapidly fatal, PCGDTL has a broad clinical spectrum that may include indolent variants—subcutaneous, epidermotropic, and dermal. Patients typically present with nodular lesions that progress to ulceration and necrosis. Early lesions can be confused with erythema nodosum, mycosis fungoides, or infection. Histologically, they show variable epidermotropism as well as dermal and subcutaneous involvement by medium to large cells with coarse clumped chromatin (Figure 4). Large blastic cells with vesicular nuclei and prominent nucleoli are infrequent. In contrast to BPCDN, the neoplastic lymphocytes in dermal and subcutaneous PCGDTL typically are positive for T-cell intracellular antigen-1 and granzyme B with loss of CD4.⁹

At the time of presentation, 27% to 87% of BPDCN patients will have bone marrow involvement, 22% to 28% will have blood involvement, and 6% to 41% will have lymph node involvement.^{1-4,6,7,10,11} The clinical course is aggressive, with a median survival of 10.0 to 19.8 months, irrespective of the initial pattern of disease.¹ Most cases have shown initial response to multiagent chemotherapy, but relapses with subsequent resistance to drugs regularly have been observed. Age has an adverse impact of prognosis. Low TdT expression has been associated with shorter survival.¹ Approximately 10% to 20% of cases of BPDCN are associated with or develop into chronic myelogenous leukemia, myelodysplastic syndrome, or acute myeloid leukemia.^1,4 Pediatric patients have a greater 5-year overall survival rate than older patients, and overall survival worsens with increasing age. The extent of cutaneous involvement and presence of systemic involvement at initial presentation do not seem to be strong predictors of survival.^{1,2,5-7,10-12} In a retrospective analysis of 90 patients, Julia et al¹² found that the type of skin disease did not predict survival. Specifically, the presence of nodular lesions and disseminated skin involvement were not adverse prognostic factors compared with macular lesions limited to 1 or 2 body areas.¹²