The Journal of Family Practice

A 48-year-old woman sought care for a widespread pruritic skin eruption that began on her upper back and spread to her arms, lower trunk, and lower legs. She’d had the rash for approximately 2 months and didn’t have any systemic symptoms. A course of prednisone prior to her presentation failed to improve the rash. She denied a personal or family history of rheumatologic or dermatologic disease and reported no new medications or exposures.

On physical exam, she was afebrile and her vital signs were normal. The rash had red-to-salmon–colored scaling patches with discrete and coalescing follicular papules. There were prominent islands of sparing (FIGURE 1).

The patient’s palms were waxy and erythematous and her feet had hyperkeratosis. A complete blood count, comprehensive metabolic panel, and lipid panel were normal. A skin biopsy demonstrated psoriasiform dermatitis with alternating areas of orthokeratosis and parakeratosis (the presence of keratinocyte nuclei within the stratum corneum where nuclei typically aren’t found).

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

Diagnosis: Pityriasis rubra pilaris

The patient was given a diagnosis of pityriasis rubra pilaris (PRP) based on her distinctive clinical presentation. This included the presence of prominent islands of sparing, the red-to-salmon scaling patches with follicular papules, the waxy erythema of her palms, and the cephalocaudal progression of her rash. The patient’s skin biopsy findings (in particular, the alternating orthokeratosis/parakeratosis) were also supportive of the diagnosis and helpful to exclude other potential causes of erythroderma (described below).

In rare cases, pityriasis rubra pilaris has been associated with internal malignancy and human immnodeficiency virus infection.PRP most often affects middle-aged individuals with an equal sex distribution. The etiology and pathogenesis of PRP are not well understood. In rare cases, it has been associated with internal malignancy and human immunodeficiency virus (HIV) infection.^1,2 PRP may stem from a combination of a dysfunction in vitamin A metabolism, genetic factors, and immune dysregulation.³ Six types of PRP have been identified; they differ in the way they present and the populations affected (TABLE).^1,4

PRP can be confused with other causes of erythroderma

PRP can cause erythroderma (also known as exfoliative dermatitis), which is the term applied to an erythematous eruption with scaling that covers ≥90% of the body’s surface area. Akhyani et al found that PRP is responsible for approximately 8% of all erythrodermas;⁵ the other causes of erythroderma are manifestations of numerous conditions, including psoriasis, dermatitis, drug eruptions, and malignancy. The course and prognosis of the erythroderma varies with the underlying condition causing it.⁶

Psoriasis is a common cause of exfoliative dermatitis in adults. Erythroderma may occur in patients with underlying psoriasis after discontinuing, or rapidly tapering, systemic corticosteroids.⁷ Because PRP is a papulosquamous eruption, it is often confused with psoriasis.^1,3

Dermatitis. Several subtypes of dermatitis can be associated with erythroderma. These include atopic, seborrheic, allergic contact, airborne, and photosensitivity dermatitis.

Drug eruptions. Numerous pharmacologic agents have been associated with the development of widespread drug-induced skin eruptions. These eruptions include the severe reaction of toxic epidermal necrolysis, which always involves sloughing of skin.

Malignancy. Both cutaneous T-cell lymphoma (including mycosis fungoides) and internal malignancies can lead to erythroderma.^6,8,9

PRP has several distinguishing features from other causes of erythroderma. The natural course of classic adult PRP (type 1) is variable, but is typically self-resolving within 3 years of onset. Clinical findings include red-to-salmon–colored follicular hyperkeratosis that forms papules or plaques with scales. There are often prominent islands of central sparing. Palmoplantar keratoderma is also commonly observed. The disease typically spreads in a cephalocaudal fashion and may progress to generalized erythroderma.¹

Treatment includes oral retinoids

In the initial evaluation of most cases of erythroderma, it is important to perform a skin biopsy (a 4-mm punch is often best) with a request for a rush reading to avoid missing a possibly severe and life-threatening diagnosis. Skin biopsy is often not diagnostic, but may show alternating parakeratosis and orthokeratosis (as in this case). Careful correlation of the histopathologic findings with the clinical presentation is what usually leads to the diagnosis. Obtaining 2 punch biopsies may be helpful if there are multiple morphologies present or if mycosis fungoides is suspected. If the patient is not physiologically stable, hospitalization is warranted.

Cases of classic adult (type 1) pityriasis rubra pilaris typically self-resolve within 3 years of onset.Oral retinoids (eg, acitretin) are the first-line treatment for PRP. PRP is a rare disease, so the best treatment data available include studies involving small case series. Other treatments include methotrexate and phototherapy, but results are mixed and patient-dependent.^1,3 In fact, some patients have experienced flare-ups when treated with phototherapy; therefore, it is not a commonly used treatment for PRP.

Tumor necrosis factor (TNF)-alpha inhibitors, including infliximab, adalimumab, and etanercept, have been used increasingly with varying degrees of success.^10-12 TNF-alpha inhibitors have a relatively good safety profile and should be considered in refractory cases. If there are associated conditions, such as HIV, treating these may also result in remission.²

Our patient was treated with oral acitretin 70 mg/d. At a 3-month follow-up visit, her skin showed signs of partial improvement. The patient was lost to follow-up.

CORRESPONDENCE
André D. Généreux, MD, Department of Internal Medicine, Abbott-Northwestern Hospital, 800 East 28th Street, Minneapolis, MN 55407-3799; [email protected].

A 48-year-old woman sought care for a widespread pruritic skin eruption that began on her upper back and spread to her arms, lower trunk, and lower legs. She’d had the rash for approximately 2 months and didn’t have any systemic symptoms. A course of prednisone prior to her presentation failed to improve the rash. She denied a personal or family history of rheumatologic or dermatologic disease and reported no new medications or exposures.

On physical exam, she was afebrile and her vital signs were normal. The rash had red-to-salmon–colored scaling patches with discrete and coalescing follicular papules. There were prominent islands of sparing (FIGURE 1).

The patient’s palms were waxy and erythematous and her feet had hyperkeratosis. A complete blood count, comprehensive metabolic panel, and lipid panel were normal. A skin biopsy demonstrated psoriasiform dermatitis with alternating areas of orthokeratosis and parakeratosis (the presence of keratinocyte nuclei within the stratum corneum where nuclei typically aren’t found).

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

Diagnosis: Pityriasis rubra pilaris

The patient was given a diagnosis of pityriasis rubra pilaris (PRP) based on her distinctive clinical presentation. This included the presence of prominent islands of sparing, the red-to-salmon scaling patches with follicular papules, the waxy erythema of her palms, and the cephalocaudal progression of her rash. The patient’s skin biopsy findings (in particular, the alternating orthokeratosis/parakeratosis) were also supportive of the diagnosis and helpful to exclude other potential causes of erythroderma (described below).

In rare cases, pityriasis rubra pilaris has been associated with internal malignancy and human immnodeficiency virus infection.PRP most often affects middle-aged individuals with an equal sex distribution. The etiology and pathogenesis of PRP are not well understood. In rare cases, it has been associated with internal malignancy and human immunodeficiency virus (HIV) infection.^1,2 PRP may stem from a combination of a dysfunction in vitamin A metabolism, genetic factors, and immune dysregulation.³ Six types of PRP have been identified; they differ in the way they present and the populations affected (TABLE).^1,4

PRP can be confused with other causes of erythroderma

PRP can cause erythroderma (also known as exfoliative dermatitis), which is the term applied to an erythematous eruption with scaling that covers ≥90% of the body’s surface area. Akhyani et al found that PRP is responsible for approximately 8% of all erythrodermas;⁵ the other causes of erythroderma are manifestations of numerous conditions, including psoriasis, dermatitis, drug eruptions, and malignancy. The course and prognosis of the erythroderma varies with the underlying condition causing it.⁶

Psoriasis is a common cause of exfoliative dermatitis in adults. Erythroderma may occur in patients with underlying psoriasis after discontinuing, or rapidly tapering, systemic corticosteroids.⁷ Because PRP is a papulosquamous eruption, it is often confused with psoriasis.^1,3

Dermatitis. Several subtypes of dermatitis can be associated with erythroderma. These include atopic, seborrheic, allergic contact, airborne, and photosensitivity dermatitis.

Drug eruptions. Numerous pharmacologic agents have been associated with the development of widespread drug-induced skin eruptions. These eruptions include the severe reaction of toxic epidermal necrolysis, which always involves sloughing of skin.

Malignancy. Both cutaneous T-cell lymphoma (including mycosis fungoides) and internal malignancies can lead to erythroderma.^6,8,9

PRP has several distinguishing features from other causes of erythroderma. The natural course of classic adult PRP (type 1) is variable, but is typically self-resolving within 3 years of onset. Clinical findings include red-to-salmon–colored follicular hyperkeratosis that forms papules or plaques with scales. There are often prominent islands of central sparing. Palmoplantar keratoderma is also commonly observed. The disease typically spreads in a cephalocaudal fashion and may progress to generalized erythroderma.¹

Treatment includes oral retinoids

In the initial evaluation of most cases of erythroderma, it is important to perform a skin biopsy (a 4-mm punch is often best) with a request for a rush reading to avoid missing a possibly severe and life-threatening diagnosis. Skin biopsy is often not diagnostic, but may show alternating parakeratosis and orthokeratosis (as in this case). Careful correlation of the histopathologic findings with the clinical presentation is what usually leads to the diagnosis. Obtaining 2 punch biopsies may be helpful if there are multiple morphologies present or if mycosis fungoides is suspected. If the patient is not physiologically stable, hospitalization is warranted.

Cases of classic adult (type 1) pityriasis rubra pilaris typically self-resolve within 3 years of onset.Oral retinoids (eg, acitretin) are the first-line treatment for PRP. PRP is a rare disease, so the best treatment data available include studies involving small case series. Other treatments include methotrexate and phototherapy, but results are mixed and patient-dependent.^1,3 In fact, some patients have experienced flare-ups when treated with phototherapy; therefore, it is not a commonly used treatment for PRP.

Tumor necrosis factor (TNF)-alpha inhibitors, including infliximab, adalimumab, and etanercept, have been used increasingly with varying degrees of success.^10-12 TNF-alpha inhibitors have a relatively good safety profile and should be considered in refractory cases. If there are associated conditions, such as HIV, treating these may also result in remission.²

Our patient was treated with oral acitretin 70 mg/d. At a 3-month follow-up visit, her skin showed signs of partial improvement. The patient was lost to follow-up.

CORRESPONDENCE
André D. Généreux, MD, Department of Internal Medicine, Abbott-Northwestern Hospital, 800 East 28th Street, Minneapolis, MN 55407-3799; [email protected].

A 48-year-old woman sought care for a widespread pruritic skin eruption that began on her upper back and spread to her arms, lower trunk, and lower legs. She’d had the rash for approximately 2 months and didn’t have any systemic symptoms. A course of prednisone prior to her presentation failed to improve the rash. She denied a personal or family history of rheumatologic or dermatologic disease and reported no new medications or exposures.

On physical exam, she was afebrile and her vital signs were normal. The rash had red-to-salmon–colored scaling patches with discrete and coalescing follicular papules. There were prominent islands of sparing (FIGURE 1).

The patient’s palms were waxy and erythematous and her feet had hyperkeratosis. A complete blood count, comprehensive metabolic panel, and lipid panel were normal. A skin biopsy demonstrated psoriasiform dermatitis with alternating areas of orthokeratosis and parakeratosis (the presence of keratinocyte nuclei within the stratum corneum where nuclei typically aren’t found).

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

Diagnosis: Pityriasis rubra pilaris

The patient was given a diagnosis of pityriasis rubra pilaris (PRP) based on her distinctive clinical presentation. This included the presence of prominent islands of sparing, the red-to-salmon scaling patches with follicular papules, the waxy erythema of her palms, and the cephalocaudal progression of her rash. The patient’s skin biopsy findings (in particular, the alternating orthokeratosis/parakeratosis) were also supportive of the diagnosis and helpful to exclude other potential causes of erythroderma (described below).

In rare cases, pityriasis rubra pilaris has been associated with internal malignancy and human immnodeficiency virus infection.PRP most often affects middle-aged individuals with an equal sex distribution. The etiology and pathogenesis of PRP are not well understood. In rare cases, it has been associated with internal malignancy and human immunodeficiency virus (HIV) infection.^1,2 PRP may stem from a combination of a dysfunction in vitamin A metabolism, genetic factors, and immune dysregulation.³ Six types of PRP have been identified; they differ in the way they present and the populations affected (TABLE).^1,4

PRP can be confused with other causes of erythroderma

PRP can cause erythroderma (also known as exfoliative dermatitis), which is the term applied to an erythematous eruption with scaling that covers ≥90% of the body’s surface area. Akhyani et al found that PRP is responsible for approximately 8% of all erythrodermas;⁵ the other causes of erythroderma are manifestations of numerous conditions, including psoriasis, dermatitis, drug eruptions, and malignancy. The course and prognosis of the erythroderma varies with the underlying condition causing it.⁶

Psoriasis is a common cause of exfoliative dermatitis in adults. Erythroderma may occur in patients with underlying psoriasis after discontinuing, or rapidly tapering, systemic corticosteroids.⁷ Because PRP is a papulosquamous eruption, it is often confused with psoriasis.^1,3

Dermatitis. Several subtypes of dermatitis can be associated with erythroderma. These include atopic, seborrheic, allergic contact, airborne, and photosensitivity dermatitis.

Drug eruptions. Numerous pharmacologic agents have been associated with the development of widespread drug-induced skin eruptions. These eruptions include the severe reaction of toxic epidermal necrolysis, which always involves sloughing of skin.

Malignancy. Both cutaneous T-cell lymphoma (including mycosis fungoides) and internal malignancies can lead to erythroderma.^6,8,9

PRP has several distinguishing features from other causes of erythroderma. The natural course of classic adult PRP (type 1) is variable, but is typically self-resolving within 3 years of onset. Clinical findings include red-to-salmon–colored follicular hyperkeratosis that forms papules or plaques with scales. There are often prominent islands of central sparing. Palmoplantar keratoderma is also commonly observed. The disease typically spreads in a cephalocaudal fashion and may progress to generalized erythroderma.¹

Treatment includes oral retinoids

In the initial evaluation of most cases of erythroderma, it is important to perform a skin biopsy (a 4-mm punch is often best) with a request for a rush reading to avoid missing a possibly severe and life-threatening diagnosis. Skin biopsy is often not diagnostic, but may show alternating parakeratosis and orthokeratosis (as in this case). Careful correlation of the histopathologic findings with the clinical presentation is what usually leads to the diagnosis. Obtaining 2 punch biopsies may be helpful if there are multiple morphologies present or if mycosis fungoides is suspected. If the patient is not physiologically stable, hospitalization is warranted.

Cases of classic adult (type 1) pityriasis rubra pilaris typically self-resolve within 3 years of onset.Oral retinoids (eg, acitretin) are the first-line treatment for PRP. PRP is a rare disease, so the best treatment data available include studies involving small case series. Other treatments include methotrexate and phototherapy, but results are mixed and patient-dependent.^1,3 In fact, some patients have experienced flare-ups when treated with phototherapy; therefore, it is not a commonly used treatment for PRP.

Tumor necrosis factor (TNF)-alpha inhibitors, including infliximab, adalimumab, and etanercept, have been used increasingly with varying degrees of success.^10-12 TNF-alpha inhibitors have a relatively good safety profile and should be considered in refractory cases. If there are associated conditions, such as HIV, treating these may also result in remission.²

Our patient was treated with oral acitretin 70 mg/d. At a 3-month follow-up visit, her skin showed signs of partial improvement. The patient was lost to follow-up.

CORRESPONDENCE
André D. Généreux, MD, Department of Internal Medicine, Abbott-Northwestern Hospital, 800 East 28th Street, Minneapolis, MN 55407-3799; [email protected].

A 4-month-old girl was brought to our clinic with a 4-week history of blisters on her arms and legs. The eruption started on her right posterior and lateral calf and then appeared on her left calf and bilateral elbows. Other than the blisters, the girl appeared well and was eating and growing normally. Her parents said she had not been in contact with anyone with a similar rash or itching. They also denied recent outdoor activities, camping trips, or environmental exposures.

The child had been previously treated with topical and oral steroids and oral antibiotics by a pediatrician, but the rash barely improved. On physical examination, she was afebrile with well-demarcated erythematous papules and plaques with bullae, and erosions with honey-colored crusts. The rash was distributed symmetrically on the bilateral posterior and lateral lower legs and lateral upper arms (FIGURE).

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

Diagnosis: Allergic contact dermatitis from a car seat

The appearance and distribution of the rash on the infant’s posterior and lateral lower legs and lateral upper arms prompted us to conclude that this was a case of allergic contact dermatitis from a car seat, along with secondary impetiginization.

The incidence of car seat contact dermatitis is unknown, although it is suspected to be both under-recognized and under-reported. In fact, the number of cases may be on the rise,¹ given the increasing number of synthetic liners now being used in car seats, high chairs, and other infant support products.

The distribution of car seat dermatitis typically involves areas in direct contact with the car seat, such as the elbows, upper lateral or posterior thighs, and lower lateral legs.More common in summer months. Car seat dermatitis is commonly reported in warmer months, when an infant’s skin is more likely to be in direct contact with the car seat and sweating is increased.¹ In the acute setting, clinical morphology usually takes the form of inflamed papules or vesicles, while in chronic presentations, lichenified eczematous plaques may be seen. Distribution is typically symmetric and involves areas in direct contact with the car seat, such as the elbows, upper lateral or posterior thighs, lower lateral legs, and sometimes, the occipital scalp.¹ The presence of a secondary infection or autoeczematization can complicate the clinical presentation.

Which car seat materials are to blame? Previous reports have described the shiny, nylon-like material overlying the car seat cushion as the cause of the contact allergy, but no specific allergens have yet been identified.¹ Attempts at identifying specific allergens in car seat liners have been thwarted by the proprietary nature of manufacturers’ formulas and the unwillingness of companies to divulge the chemicals used in the manufacture of their car seats. Potential allergens include bromine, chlorine, and flame-retardants.¹ These allergens differ from the usual contact allergens in children and adolescents, which include nickel sulfate, cobalt chloride, potassium dichromate, fragrance mix, thimerosal, neomycin sulfate, and para-tertiary-butylphenol formaldehyde resin.²

Differential includes other conditions with blisters, plaques

The differential diagnosis includes eczema herpeticum, bullous impetigo, and psoriasis.

Infants with eczema herpeticum usually have eczematous plaques in locations such as the cheeks, neck, antecubital fossa, popliteal fossa, and ankles, with numerous “punched-out” shallow erosions. Children with extensive eczema herpeticum can be systemically ill.

Bullous impetigo is seen as flaccid bullae in infants, which can easily rupture and leave behind superficial erosions. These blisters tend to appear on normal skin. (This is quite different from the thick, erythematous plaques seen in contact dermatitis.) In patients with superficial erosions, a polymerase chain reaction test for the herpes virus and a bacterial culture should be obtained.

Psoriasis often presents with well-demarcated erythematous plaques with overlying silver scale. Although it can be symmetric on extensor surfaces, the weeping vesicles with acute onset that were seen in this case would be unusual.

Look for a pattern. The well-demarcated symmetric plaques corresponding directly to areas in contact with the car seat should be a strong clue for contact dermatitis. While patch testing for relevant chemicals is often indicated in patients for whom there is a clinical suspicion of a contact allergy,^3,4 we did not perform such testing because the specific chemicals involved in car seat manufacturing are unknown.

Topical steroids and avoidance of the allergen help resolve the rash

The mainstay of treatment for allergic contact dermatitis is avoiding the contact allergen. In car seat contact dermatitis, parents should be counseled to avoid contact between the child’s bare skin and the car seat liner. Given that the precise allergen is unknown, it is impossible to know if a new car seat would contain the same material. Instead, we recommend covering the car seat with a cotton blanket to avoid irritation/allergens.

Depending on the extent of the rash, the patient should be treated with a mid- or high-potency topical steroid until the erythema and blistering resolve.^5-8 A 3-week prednisone taper can also be considered for severe cases. For patients who have >25% of their body surface involved, oral steroids are recommended.⁶ Any secondary infection should be treated with topical and oral antibiotics, as appropriate.

Our patient. Due to the extent and severity of the eruption, we put the patient on a 3-week oral prednisone taper and advised the parents to apply clobetasol 0.05% ointment to the affected areas 2 times a day. We also prescribed a 7-day course of cephalexin 50 mg/kg divided in 3 doses a day and topical mupirocin ointment (to be applied 2 times a day) for the secondary impetiginization.

We advised the parents to use a cotton blanket over the baby’s car seat to prevent further outbreaks. The eruption resolved within 2 months. 

CORRESPONDENCE
Karolyn A. Wanat, MD, Department of Dermatology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, 40000 PFP, Iowa City, IA 52242; [email protected].

A 4-month-old girl was brought to our clinic with a 4-week history of blisters on her arms and legs. The eruption started on her right posterior and lateral calf and then appeared on her left calf and bilateral elbows. Other than the blisters, the girl appeared well and was eating and growing normally. Her parents said she had not been in contact with anyone with a similar rash or itching. They also denied recent outdoor activities, camping trips, or environmental exposures.

The child had been previously treated with topical and oral steroids and oral antibiotics by a pediatrician, but the rash barely improved. On physical examination, she was afebrile with well-demarcated erythematous papules and plaques with bullae, and erosions with honey-colored crusts. The rash was distributed symmetrically on the bilateral posterior and lateral lower legs and lateral upper arms (FIGURE).

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

Diagnosis: Allergic contact dermatitis from a car seat

The appearance and distribution of the rash on the infant’s posterior and lateral lower legs and lateral upper arms prompted us to conclude that this was a case of allergic contact dermatitis from a car seat, along with secondary impetiginization.

The incidence of car seat contact dermatitis is unknown, although it is suspected to be both under-recognized and under-reported. In fact, the number of cases may be on the rise,¹ given the increasing number of synthetic liners now being used in car seats, high chairs, and other infant support products.

The distribution of car seat dermatitis typically involves areas in direct contact with the car seat, such as the elbows, upper lateral or posterior thighs, and lower lateral legs.More common in summer months. Car seat dermatitis is commonly reported in warmer months, when an infant’s skin is more likely to be in direct contact with the car seat and sweating is increased.¹ In the acute setting, clinical morphology usually takes the form of inflamed papules or vesicles, while in chronic presentations, lichenified eczematous plaques may be seen. Distribution is typically symmetric and involves areas in direct contact with the car seat, such as the elbows, upper lateral or posterior thighs, lower lateral legs, and sometimes, the occipital scalp.¹ The presence of a secondary infection or autoeczematization can complicate the clinical presentation.

Which car seat materials are to blame? Previous reports have described the shiny, nylon-like material overlying the car seat cushion as the cause of the contact allergy, but no specific allergens have yet been identified.¹ Attempts at identifying specific allergens in car seat liners have been thwarted by the proprietary nature of manufacturers’ formulas and the unwillingness of companies to divulge the chemicals used in the manufacture of their car seats. Potential allergens include bromine, chlorine, and flame-retardants.¹ These allergens differ from the usual contact allergens in children and adolescents, which include nickel sulfate, cobalt chloride, potassium dichromate, fragrance mix, thimerosal, neomycin sulfate, and para-tertiary-butylphenol formaldehyde resin.²

Differential includes other conditions with blisters, plaques

The differential diagnosis includes eczema herpeticum, bullous impetigo, and psoriasis.

Infants with eczema herpeticum usually have eczematous plaques in locations such as the cheeks, neck, antecubital fossa, popliteal fossa, and ankles, with numerous “punched-out” shallow erosions. Children with extensive eczema herpeticum can be systemically ill.

Bullous impetigo is seen as flaccid bullae in infants, which can easily rupture and leave behind superficial erosions. These blisters tend to appear on normal skin. (This is quite different from the thick, erythematous plaques seen in contact dermatitis.) In patients with superficial erosions, a polymerase chain reaction test for the herpes virus and a bacterial culture should be obtained.

Psoriasis often presents with well-demarcated erythematous plaques with overlying silver scale. Although it can be symmetric on extensor surfaces, the weeping vesicles with acute onset that were seen in this case would be unusual.

Look for a pattern. The well-demarcated symmetric plaques corresponding directly to areas in contact with the car seat should be a strong clue for contact dermatitis. While patch testing for relevant chemicals is often indicated in patients for whom there is a clinical suspicion of a contact allergy,^3,4 we did not perform such testing because the specific chemicals involved in car seat manufacturing are unknown.

Topical steroids and avoidance of the allergen help resolve the rash

The mainstay of treatment for allergic contact dermatitis is avoiding the contact allergen. In car seat contact dermatitis, parents should be counseled to avoid contact between the child’s bare skin and the car seat liner. Given that the precise allergen is unknown, it is impossible to know if a new car seat would contain the same material. Instead, we recommend covering the car seat with a cotton blanket to avoid irritation/allergens.

Depending on the extent of the rash, the patient should be treated with a mid- or high-potency topical steroid until the erythema and blistering resolve.^5-8 A 3-week prednisone taper can also be considered for severe cases. For patients who have >25% of their body surface involved, oral steroids are recommended.⁶ Any secondary infection should be treated with topical and oral antibiotics, as appropriate.

Our patient. Due to the extent and severity of the eruption, we put the patient on a 3-week oral prednisone taper and advised the parents to apply clobetasol 0.05% ointment to the affected areas 2 times a day. We also prescribed a 7-day course of cephalexin 50 mg/kg divided in 3 doses a day and topical mupirocin ointment (to be applied 2 times a day) for the secondary impetiginization.

We advised the parents to use a cotton blanket over the baby’s car seat to prevent further outbreaks. The eruption resolved within 2 months. 

CORRESPONDENCE
Karolyn A. Wanat, MD, Department of Dermatology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, 40000 PFP, Iowa City, IA 52242; [email protected].

A 4-month-old girl was brought to our clinic with a 4-week history of blisters on her arms and legs. The eruption started on her right posterior and lateral calf and then appeared on her left calf and bilateral elbows. Other than the blisters, the girl appeared well and was eating and growing normally. Her parents said she had not been in contact with anyone with a similar rash or itching. They also denied recent outdoor activities, camping trips, or environmental exposures.

The child had been previously treated with topical and oral steroids and oral antibiotics by a pediatrician, but the rash barely improved. On physical examination, she was afebrile with well-demarcated erythematous papules and plaques with bullae, and erosions with honey-colored crusts. The rash was distributed symmetrically on the bilateral posterior and lateral lower legs and lateral upper arms (FIGURE).

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

Diagnosis: Allergic contact dermatitis from a car seat

The appearance and distribution of the rash on the infant’s posterior and lateral lower legs and lateral upper arms prompted us to conclude that this was a case of allergic contact dermatitis from a car seat, along with secondary impetiginization.

The incidence of car seat contact dermatitis is unknown, although it is suspected to be both under-recognized and under-reported. In fact, the number of cases may be on the rise,¹ given the increasing number of synthetic liners now being used in car seats, high chairs, and other infant support products.

The distribution of car seat dermatitis typically involves areas in direct contact with the car seat, such as the elbows, upper lateral or posterior thighs, and lower lateral legs.More common in summer months. Car seat dermatitis is commonly reported in warmer months, when an infant’s skin is more likely to be in direct contact with the car seat and sweating is increased.¹ In the acute setting, clinical morphology usually takes the form of inflamed papules or vesicles, while in chronic presentations, lichenified eczematous plaques may be seen. Distribution is typically symmetric and involves areas in direct contact with the car seat, such as the elbows, upper lateral or posterior thighs, lower lateral legs, and sometimes, the occipital scalp.¹ The presence of a secondary infection or autoeczematization can complicate the clinical presentation.

Which car seat materials are to blame? Previous reports have described the shiny, nylon-like material overlying the car seat cushion as the cause of the contact allergy, but no specific allergens have yet been identified.¹ Attempts at identifying specific allergens in car seat liners have been thwarted by the proprietary nature of manufacturers’ formulas and the unwillingness of companies to divulge the chemicals used in the manufacture of their car seats. Potential allergens include bromine, chlorine, and flame-retardants.¹ These allergens differ from the usual contact allergens in children and adolescents, which include nickel sulfate, cobalt chloride, potassium dichromate, fragrance mix, thimerosal, neomycin sulfate, and para-tertiary-butylphenol formaldehyde resin.²

Differential includes other conditions with blisters, plaques

The differential diagnosis includes eczema herpeticum, bullous impetigo, and psoriasis.

Infants with eczema herpeticum usually have eczematous plaques in locations such as the cheeks, neck, antecubital fossa, popliteal fossa, and ankles, with numerous “punched-out” shallow erosions. Children with extensive eczema herpeticum can be systemically ill.

Bullous impetigo is seen as flaccid bullae in infants, which can easily rupture and leave behind superficial erosions. These blisters tend to appear on normal skin. (This is quite different from the thick, erythematous plaques seen in contact dermatitis.) In patients with superficial erosions, a polymerase chain reaction test for the herpes virus and a bacterial culture should be obtained.

Psoriasis often presents with well-demarcated erythematous plaques with overlying silver scale. Although it can be symmetric on extensor surfaces, the weeping vesicles with acute onset that were seen in this case would be unusual.

Look for a pattern. The well-demarcated symmetric plaques corresponding directly to areas in contact with the car seat should be a strong clue for contact dermatitis. While patch testing for relevant chemicals is often indicated in patients for whom there is a clinical suspicion of a contact allergy,^3,4 we did not perform such testing because the specific chemicals involved in car seat manufacturing are unknown.

Topical steroids and avoidance of the allergen help resolve the rash

The mainstay of treatment for allergic contact dermatitis is avoiding the contact allergen. In car seat contact dermatitis, parents should be counseled to avoid contact between the child’s bare skin and the car seat liner. Given that the precise allergen is unknown, it is impossible to know if a new car seat would contain the same material. Instead, we recommend covering the car seat with a cotton blanket to avoid irritation/allergens.

Depending on the extent of the rash, the patient should be treated with a mid- or high-potency topical steroid until the erythema and blistering resolve.^5-8 A 3-week prednisone taper can also be considered for severe cases. For patients who have >25% of their body surface involved, oral steroids are recommended.⁶ Any secondary infection should be treated with topical and oral antibiotics, as appropriate.

Our patient. Due to the extent and severity of the eruption, we put the patient on a 3-week oral prednisone taper and advised the parents to apply clobetasol 0.05% ointment to the affected areas 2 times a day. We also prescribed a 7-day course of cephalexin 50 mg/kg divided in 3 doses a day and topical mupirocin ointment (to be applied 2 times a day) for the secondary impetiginization.

We advised the parents to use a cotton blanket over the baby’s car seat to prevent further outbreaks. The eruption resolved within 2 months. 

CORRESPONDENCE
Karolyn A. Wanat, MD, Department of Dermatology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, 40000 PFP, Iowa City, IA 52242; [email protected].

THE CASE

A 76-year-old Caucasian woman presented to the emergency department with a 7-day history of weakness and pain in her arms and legs. She had a history of Candida albicans vertebral osteomyelitis that had been treated for 3 months with fluconazole; non-Hodgkin lymphoma that had been in remission for 6 months; diabetes mellitus; hyperlipidemia; and hypothyroidism. The woman had dark urine, but denied chills, fever, respiratory symptoms, bowel or bladder leakage, falls/trauma, or grapefruit juice intake.

Her current medications included oral fluconazole 400 mg/d, simvastatin 20 mg/d, levothyroxine 88 mcg/d, pregabalin 75 mg/d, metformin 1000 mg twice daily, 6 units of subcutaneous insulin glargine at bedtime, and 2 units of insulin lispro with each meal. During the examination, we noted marked proximal muscle weakness, significant tenderness in all extremities, and diminished deep tendon reflexes. The patient had no saddle anesthesia, impaired rectal tone, or sensory abnormalities.

THE DIAGNOSIS

Magnetic resonance imaging of the patient’s spine confirmed multilevel discitis and osteomyelitis (T7-T9, L5-S1) with no cord compression. Laboratory data included a creatinine level of 1.42 mg/dL (the patient’s baseline was 0.8 mg/dL); a creatine kinase (CK) level of 8876 U/L (normal range, 0-220 U/L); a thyroid-stimulating hormone (TSH) level of 9.35 mIU/L (normal range, 0.4-5.5 mIU/L); and an erythrocyte sedimentation rate of 27 mm/hr (normal range, 0-31 mm/hr).

The patient received aggressive fluid hydration, orally and intravenously. On Day 2, the patient’s serum myoglobin level was 14,301 ng/mL (normal range, 30-90 ng/mL) and her aldolase level was 87.6 U/L (normal range, 1.5-8.5 U/L).

Zeroing in on the cause. There were no signs of drug abuse or use of other non-statin culprit medications that could have caused the patient’s rhabdomyolysis. She also did not describe any triggers of rhabdomyolysis, such as trauma, viral infection, metabolic disturbances, or temperature dysregulation. We believed the most likely cause of our patient’s signs and symptoms was statin-induced rhabdomyolysis, likely due to an interaction between simvastatin and fluconazole. We considered hypothyroidism-induced rhabdomyolysis, but thought it was unlikely because the patient had a mildly increased TSH level on admission, and one would expect to see levels higher than 100 mIU/L.^1-3

We also considered viral myositis in the differential, but it was an unlikely culprit because the patient lacked any history of fever or respiratory or gastrointestinal symptoms. And while paraneoplastic polymyositis could have caused the patient’s weakness, the marked muscle pain and acute kidney injury were far more suggestive of rhabdomyolysis.

DISCUSSION

Rhabdomyolysis is a serious complication of statin treatment. Both higher statin doses and pharmacokinetic factors can raise statin levels, leading to this serious muscle-related syndrome.^4,5 Co-administration of statins with drugs that are strong inhibitors of cytochrome P450 (CYP) 3A4 (the main cytochrome P450 isoform that metabolizes most statins) can increase statin levels several fold.^6,7 The trigger for our patient’s statin-induced rhabdomyolysis was fluconazole, a known moderate inhibitor of CYP3A4, which is comparatively weaker than certain potent azoles like itraconazole or ketoconazole.^7-10 Doses of fluconazole generally ≥200 mg/d are needed to produce clinical interactions with CYP3A4 substrates.⁷ There are only 3 reported cases of fluconazole-simvastatin–induced rhabdomyolysis (TABLE 1).^11-13

The Food and Drug Administration advises against simvastatin co-prescription with itraconazole and ketoconazole, but doesn’t mention fluconazole in its Drug Safety communication on simvastatin.¹⁴

Lexicomp places the simvastatin-fluconazole drug interaction into category C, which means that the agents can interact in a clinically significant manner (and a monitoring plan should be implemented), but that the benefits of concomitant use usually outweigh the risks.¹⁵

How our patient’s case differs from previous cases

Several features distinguish our patient’s scenario from previous cases. First, unlike other cases in which both drugs were stopped, only simvastatin was discontinued in our patient. Simvastatin and fluconazole have a half-life of 3 hours⁶ and 32 hours,⁷ respectively, suggesting that when simvastatin has fully cleared, fluconazole’s concentration will not even have halved. Thus, fluconazole was safely continued to treat the patient’s osteomyelitis.

Second, compared to previous case reports, our patient was taking a lower dose of simvastatin (20 mg). A 20-mg dose can make the drug interaction easier to miss; pharmacists are more likely to inform the physician of a potential drug interaction when the dose of a statin is ≥40 mg compared to when it is <40 mg (odds ratio=1.89; 95% confidence interval, 0.98-3.63).¹⁶

Researchers involved in the British randomized trial SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine) sought to evaluate any added benefit to a higher dose of simvastatin in post-myocardial infarction patients. Among approximately 12,000 patients in the trial, there were 7 cases of rhabdomyolysis for the 80-mg simvastatin group and none for the 20-mg group.⁵ Another large case-control study showed that a 40-mg simvastatin dose was 5 times more likely to cause rhabdomyolysis than a 20-mg dose.¹⁷ Yet, based on our patient’s case, even 20 mg/d simvastatin should not decrease physician suspicion for rhabdomyolysis if patients are also taking a CYP3A4 inhibitor.

Third, the simvastatin-fluconazole co-administration time in our patient was 12 weeks, which is longer than previously reported (TABLE 1^11-13). Azole inhibition of CYP450 occurs relatively rapidly, but that does not mean that rhabdomyolysis will always occur immediately. For example, in cases of statin monotherapy, rhabdomyolysis secondary to statin biochemical toxicity can occur up to 1050 (mean=348) days after the drug’s initiation.¹⁸

Avoiding a drug-drug interaction in your patient

Physicians can use pharmacokinetic profiles to choose among different statins and azoles to help avoid a drug interaction (TABLE 2^6,7,10,19). Pravastatin’s serum concentration, for example, is not influenced by CYP3A4 inhibitors such as itraconazole¹¹ because pravastatin is metabolized by sulfation⁶ and not by the CYP450 system. Rosuvastatin and pitavastatin are minimally metabolized by the CYP450 system.^19,20

Even 20 mg/d simvastatin should not diminish your suspicion for rhabdomyolysis if a patient is taking a CYP3A4 inhibitor.

Among approximately 2700 statin-treated outpatients,⁴ the prevalence of potentially harmful statin interactions with other drugs (including CYP3A4 inhibitors), was significantly higher among patients treated with simvastatin or atorvastatin (CYP3A4-metabolized statins), than among patients treated with fluvastatin (CYP2C9-metabolized statin) or pravastatin (metabolized by sulfation). Apart from drug-drug interactions, other risk factors for statin-induced rhabdomyolysis include use of lipophilic statins, advanced age, and female gender.²¹

We discontinued our patient’s simvastatin on the day she was admitted to the hospital, but continued with the fluconazole throughout her hospitalization. Her CK level continued to rise, peaked on hospital Day 3 at 32,886 U/L, and then progressively decreased. The patient’s weakness and pain improved and her acute kidney injury resolved with hydration. She was discharged on hospital Day 7 on oral fluconazole, but no statin, and her muscle symptoms have since resolved.

THE TAKEAWAY

When hyperlipidemic patients have to take an azole for an extended period (eg, cancer prophylaxis or chronic osteomyelitis) and the azole is a strong CYP450 inhibitor (eg, itraconazole), switching to a statin that is not primarily metabolized by the CYP450 system (eg, pravastatin, pitavastatin) is wise. If the azole is a moderate CYP450 inhibitor (eg, fluconazole), we suggest that therapy should be closely monitored. In the case of short-term azole treatment (eg, such as for oral candidiasis), the statin should be stopped or the dose reduced by at least 50% (eg, from 40 or 20 mg to 10 mg).⁶

Prescriber knowledge is sometimes a limiting factor in identifying clinically significant interactions.²² This is especially pertinent in a case like this one, where a lower statin dose may result in a lower chance of the pharmacist alerting the prescribing physician¹⁶ and when an azole is used that is a comparatively weaker CYP450 inhibitor than other azoles such as itraconazole. Even in the era of electronic medical records, approximately 90% of drug interaction alerts are overridden by physicians, and alert fatigue is pronounced.²³

The intricacies and pharmacokinetic principles of this case should contribute to greater provider familiarity with even low-dose simvastatin-fluconazole interactions and help prevent iatrogenic complications such as rhabdomyolysis.

THE CASE

A 76-year-old Caucasian woman presented to the emergency department with a 7-day history of weakness and pain in her arms and legs. She had a history of Candida albicans vertebral osteomyelitis that had been treated for 3 months with fluconazole; non-Hodgkin lymphoma that had been in remission for 6 months; diabetes mellitus; hyperlipidemia; and hypothyroidism. The woman had dark urine, but denied chills, fever, respiratory symptoms, bowel or bladder leakage, falls/trauma, or grapefruit juice intake.

Her current medications included oral fluconazole 400 mg/d, simvastatin 20 mg/d, levothyroxine 88 mcg/d, pregabalin 75 mg/d, metformin 1000 mg twice daily, 6 units of subcutaneous insulin glargine at bedtime, and 2 units of insulin lispro with each meal. During the examination, we noted marked proximal muscle weakness, significant tenderness in all extremities, and diminished deep tendon reflexes. The patient had no saddle anesthesia, impaired rectal tone, or sensory abnormalities.

THE DIAGNOSIS

Magnetic resonance imaging of the patient’s spine confirmed multilevel discitis and osteomyelitis (T7-T9, L5-S1) with no cord compression. Laboratory data included a creatinine level of 1.42 mg/dL (the patient’s baseline was 0.8 mg/dL); a creatine kinase (CK) level of 8876 U/L (normal range, 0-220 U/L); a thyroid-stimulating hormone (TSH) level of 9.35 mIU/L (normal range, 0.4-5.5 mIU/L); and an erythrocyte sedimentation rate of 27 mm/hr (normal range, 0-31 mm/hr).

The patient received aggressive fluid hydration, orally and intravenously. On Day 2, the patient’s serum myoglobin level was 14,301 ng/mL (normal range, 30-90 ng/mL) and her aldolase level was 87.6 U/L (normal range, 1.5-8.5 U/L).

Zeroing in on the cause. There were no signs of drug abuse or use of other non-statin culprit medications that could have caused the patient’s rhabdomyolysis. She also did not describe any triggers of rhabdomyolysis, such as trauma, viral infection, metabolic disturbances, or temperature dysregulation. We believed the most likely cause of our patient’s signs and symptoms was statin-induced rhabdomyolysis, likely due to an interaction between simvastatin and fluconazole. We considered hypothyroidism-induced rhabdomyolysis, but thought it was unlikely because the patient had a mildly increased TSH level on admission, and one would expect to see levels higher than 100 mIU/L.^1-3

We also considered viral myositis in the differential, but it was an unlikely culprit because the patient lacked any history of fever or respiratory or gastrointestinal symptoms. And while paraneoplastic polymyositis could have caused the patient’s weakness, the marked muscle pain and acute kidney injury were far more suggestive of rhabdomyolysis.

DISCUSSION

Rhabdomyolysis is a serious complication of statin treatment. Both higher statin doses and pharmacokinetic factors can raise statin levels, leading to this serious muscle-related syndrome.^4,5 Co-administration of statins with drugs that are strong inhibitors of cytochrome P450 (CYP) 3A4 (the main cytochrome P450 isoform that metabolizes most statins) can increase statin levels several fold.^6,7 The trigger for our patient’s statin-induced rhabdomyolysis was fluconazole, a known moderate inhibitor of CYP3A4, which is comparatively weaker than certain potent azoles like itraconazole or ketoconazole.^7-10 Doses of fluconazole generally ≥200 mg/d are needed to produce clinical interactions with CYP3A4 substrates.⁷ There are only 3 reported cases of fluconazole-simvastatin–induced rhabdomyolysis (TABLE 1).^11-13

The Food and Drug Administration advises against simvastatin co-prescription with itraconazole and ketoconazole, but doesn’t mention fluconazole in its Drug Safety communication on simvastatin.¹⁴

Lexicomp places the simvastatin-fluconazole drug interaction into category C, which means that the agents can interact in a clinically significant manner (and a monitoring plan should be implemented), but that the benefits of concomitant use usually outweigh the risks.¹⁵

How our patient’s case differs from previous cases

Several features distinguish our patient’s scenario from previous cases. First, unlike other cases in which both drugs were stopped, only simvastatin was discontinued in our patient. Simvastatin and fluconazole have a half-life of 3 hours⁶ and 32 hours,⁷ respectively, suggesting that when simvastatin has fully cleared, fluconazole’s concentration will not even have halved. Thus, fluconazole was safely continued to treat the patient’s osteomyelitis.

Second, compared to previous case reports, our patient was taking a lower dose of simvastatin (20 mg). A 20-mg dose can make the drug interaction easier to miss; pharmacists are more likely to inform the physician of a potential drug interaction when the dose of a statin is ≥40 mg compared to when it is <40 mg (odds ratio=1.89; 95% confidence interval, 0.98-3.63).¹⁶

Researchers involved in the British randomized trial SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine) sought to evaluate any added benefit to a higher dose of simvastatin in post-myocardial infarction patients. Among approximately 12,000 patients in the trial, there were 7 cases of rhabdomyolysis for the 80-mg simvastatin group and none for the 20-mg group.⁵ Another large case-control study showed that a 40-mg simvastatin dose was 5 times more likely to cause rhabdomyolysis than a 20-mg dose.¹⁷ Yet, based on our patient’s case, even 20 mg/d simvastatin should not decrease physician suspicion for rhabdomyolysis if patients are also taking a CYP3A4 inhibitor.

Third, the simvastatin-fluconazole co-administration time in our patient was 12 weeks, which is longer than previously reported (TABLE 1^11-13). Azole inhibition of CYP450 occurs relatively rapidly, but that does not mean that rhabdomyolysis will always occur immediately. For example, in cases of statin monotherapy, rhabdomyolysis secondary to statin biochemical toxicity can occur up to 1050 (mean=348) days after the drug’s initiation.¹⁸

Avoiding a drug-drug interaction in your patient

Physicians can use pharmacokinetic profiles to choose among different statins and azoles to help avoid a drug interaction (TABLE 2^6,7,10,19). Pravastatin’s serum concentration, for example, is not influenced by CYP3A4 inhibitors such as itraconazole¹¹ because pravastatin is metabolized by sulfation⁶ and not by the CYP450 system. Rosuvastatin and pitavastatin are minimally metabolized by the CYP450 system.^19,20

Even 20 mg/d simvastatin should not diminish your suspicion for rhabdomyolysis if a patient is taking a CYP3A4 inhibitor.

Among approximately 2700 statin-treated outpatients,⁴ the prevalence of potentially harmful statin interactions with other drugs (including CYP3A4 inhibitors), was significantly higher among patients treated with simvastatin or atorvastatin (CYP3A4-metabolized statins), than among patients treated with fluvastatin (CYP2C9-metabolized statin) or pravastatin (metabolized by sulfation). Apart from drug-drug interactions, other risk factors for statin-induced rhabdomyolysis include use of lipophilic statins, advanced age, and female gender.²¹

We discontinued our patient’s simvastatin on the day she was admitted to the hospital, but continued with the fluconazole throughout her hospitalization. Her CK level continued to rise, peaked on hospital Day 3 at 32,886 U/L, and then progressively decreased. The patient’s weakness and pain improved and her acute kidney injury resolved with hydration. She was discharged on hospital Day 7 on oral fluconazole, but no statin, and her muscle symptoms have since resolved.

THE TAKEAWAY

When hyperlipidemic patients have to take an azole for an extended period (eg, cancer prophylaxis or chronic osteomyelitis) and the azole is a strong CYP450 inhibitor (eg, itraconazole), switching to a statin that is not primarily metabolized by the CYP450 system (eg, pravastatin, pitavastatin) is wise. If the azole is a moderate CYP450 inhibitor (eg, fluconazole), we suggest that therapy should be closely monitored. In the case of short-term azole treatment (eg, such as for oral candidiasis), the statin should be stopped or the dose reduced by at least 50% (eg, from 40 or 20 mg to 10 mg).⁶

Prescriber knowledge is sometimes a limiting factor in identifying clinically significant interactions.²² This is especially pertinent in a case like this one, where a lower statin dose may result in a lower chance of the pharmacist alerting the prescribing physician¹⁶ and when an azole is used that is a comparatively weaker CYP450 inhibitor than other azoles such as itraconazole. Even in the era of electronic medical records, approximately 90% of drug interaction alerts are overridden by physicians, and alert fatigue is pronounced.²³

The intricacies and pharmacokinetic principles of this case should contribute to greater provider familiarity with even low-dose simvastatin-fluconazole interactions and help prevent iatrogenic complications such as rhabdomyolysis.

THE CASE

A 76-year-old Caucasian woman presented to the emergency department with a 7-day history of weakness and pain in her arms and legs. She had a history of Candida albicans vertebral osteomyelitis that had been treated for 3 months with fluconazole; non-Hodgkin lymphoma that had been in remission for 6 months; diabetes mellitus; hyperlipidemia; and hypothyroidism. The woman had dark urine, but denied chills, fever, respiratory symptoms, bowel or bladder leakage, falls/trauma, or grapefruit juice intake.

Her current medications included oral fluconazole 400 mg/d, simvastatin 20 mg/d, levothyroxine 88 mcg/d, pregabalin 75 mg/d, metformin 1000 mg twice daily, 6 units of subcutaneous insulin glargine at bedtime, and 2 units of insulin lispro with each meal. During the examination, we noted marked proximal muscle weakness, significant tenderness in all extremities, and diminished deep tendon reflexes. The patient had no saddle anesthesia, impaired rectal tone, or sensory abnormalities.

THE DIAGNOSIS

Magnetic resonance imaging of the patient’s spine confirmed multilevel discitis and osteomyelitis (T7-T9, L5-S1) with no cord compression. Laboratory data included a creatinine level of 1.42 mg/dL (the patient’s baseline was 0.8 mg/dL); a creatine kinase (CK) level of 8876 U/L (normal range, 0-220 U/L); a thyroid-stimulating hormone (TSH) level of 9.35 mIU/L (normal range, 0.4-5.5 mIU/L); and an erythrocyte sedimentation rate of 27 mm/hr (normal range, 0-31 mm/hr).

The patient received aggressive fluid hydration, orally and intravenously. On Day 2, the patient’s serum myoglobin level was 14,301 ng/mL (normal range, 30-90 ng/mL) and her aldolase level was 87.6 U/L (normal range, 1.5-8.5 U/L).

Zeroing in on the cause. There were no signs of drug abuse or use of other non-statin culprit medications that could have caused the patient’s rhabdomyolysis. She also did not describe any triggers of rhabdomyolysis, such as trauma, viral infection, metabolic disturbances, or temperature dysregulation. We believed the most likely cause of our patient’s signs and symptoms was statin-induced rhabdomyolysis, likely due to an interaction between simvastatin and fluconazole. We considered hypothyroidism-induced rhabdomyolysis, but thought it was unlikely because the patient had a mildly increased TSH level on admission, and one would expect to see levels higher than 100 mIU/L.^1-3

We also considered viral myositis in the differential, but it was an unlikely culprit because the patient lacked any history of fever or respiratory or gastrointestinal symptoms. And while paraneoplastic polymyositis could have caused the patient’s weakness, the marked muscle pain and acute kidney injury were far more suggestive of rhabdomyolysis.

DISCUSSION

Rhabdomyolysis is a serious complication of statin treatment. Both higher statin doses and pharmacokinetic factors can raise statin levels, leading to this serious muscle-related syndrome.^4,5 Co-administration of statins with drugs that are strong inhibitors of cytochrome P450 (CYP) 3A4 (the main cytochrome P450 isoform that metabolizes most statins) can increase statin levels several fold.^6,7 The trigger for our patient’s statin-induced rhabdomyolysis was fluconazole, a known moderate inhibitor of CYP3A4, which is comparatively weaker than certain potent azoles like itraconazole or ketoconazole.^7-10 Doses of fluconazole generally ≥200 mg/d are needed to produce clinical interactions with CYP3A4 substrates.⁷ There are only 3 reported cases of fluconazole-simvastatin–induced rhabdomyolysis (TABLE 1).^11-13

The Food and Drug Administration advises against simvastatin co-prescription with itraconazole and ketoconazole, but doesn’t mention fluconazole in its Drug Safety communication on simvastatin.¹⁴

Lexicomp places the simvastatin-fluconazole drug interaction into category C, which means that the agents can interact in a clinically significant manner (and a monitoring plan should be implemented), but that the benefits of concomitant use usually outweigh the risks.¹⁵

How our patient’s case differs from previous cases

Several features distinguish our patient’s scenario from previous cases. First, unlike other cases in which both drugs were stopped, only simvastatin was discontinued in our patient. Simvastatin and fluconazole have a half-life of 3 hours⁶ and 32 hours,⁷ respectively, suggesting that when simvastatin has fully cleared, fluconazole’s concentration will not even have halved. Thus, fluconazole was safely continued to treat the patient’s osteomyelitis.

Second, compared to previous case reports, our patient was taking a lower dose of simvastatin (20 mg). A 20-mg dose can make the drug interaction easier to miss; pharmacists are more likely to inform the physician of a potential drug interaction when the dose of a statin is ≥40 mg compared to when it is <40 mg (odds ratio=1.89; 95% confidence interval, 0.98-3.63).¹⁶

Researchers involved in the British randomized trial SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine) sought to evaluate any added benefit to a higher dose of simvastatin in post-myocardial infarction patients. Among approximately 12,000 patients in the trial, there were 7 cases of rhabdomyolysis for the 80-mg simvastatin group and none for the 20-mg group.⁵ Another large case-control study showed that a 40-mg simvastatin dose was 5 times more likely to cause rhabdomyolysis than a 20-mg dose.¹⁷ Yet, based on our patient’s case, even 20 mg/d simvastatin should not decrease physician suspicion for rhabdomyolysis if patients are also taking a CYP3A4 inhibitor.

Third, the simvastatin-fluconazole co-administration time in our patient was 12 weeks, which is longer than previously reported (TABLE 1^11-13). Azole inhibition of CYP450 occurs relatively rapidly, but that does not mean that rhabdomyolysis will always occur immediately. For example, in cases of statin monotherapy, rhabdomyolysis secondary to statin biochemical toxicity can occur up to 1050 (mean=348) days after the drug’s initiation.¹⁸

Avoiding a drug-drug interaction in your patient

Physicians can use pharmacokinetic profiles to choose among different statins and azoles to help avoid a drug interaction (TABLE 2^6,7,10,19). Pravastatin’s serum concentration, for example, is not influenced by CYP3A4 inhibitors such as itraconazole¹¹ because pravastatin is metabolized by sulfation⁶ and not by the CYP450 system. Rosuvastatin and pitavastatin are minimally metabolized by the CYP450 system.^19,20

Even 20 mg/d simvastatin should not diminish your suspicion for rhabdomyolysis if a patient is taking a CYP3A4 inhibitor.

Among approximately 2700 statin-treated outpatients,⁴ the prevalence of potentially harmful statin interactions with other drugs (including CYP3A4 inhibitors), was significantly higher among patients treated with simvastatin or atorvastatin (CYP3A4-metabolized statins), than among patients treated with fluvastatin (CYP2C9-metabolized statin) or pravastatin (metabolized by sulfation). Apart from drug-drug interactions, other risk factors for statin-induced rhabdomyolysis include use of lipophilic statins, advanced age, and female gender.²¹

We discontinued our patient’s simvastatin on the day she was admitted to the hospital, but continued with the fluconazole throughout her hospitalization. Her CK level continued to rise, peaked on hospital Day 3 at 32,886 U/L, and then progressively decreased. The patient’s weakness and pain improved and her acute kidney injury resolved with hydration. She was discharged on hospital Day 7 on oral fluconazole, but no statin, and her muscle symptoms have since resolved.

THE TAKEAWAY

When hyperlipidemic patients have to take an azole for an extended period (eg, cancer prophylaxis or chronic osteomyelitis) and the azole is a strong CYP450 inhibitor (eg, itraconazole), switching to a statin that is not primarily metabolized by the CYP450 system (eg, pravastatin, pitavastatin) is wise. If the azole is a moderate CYP450 inhibitor (eg, fluconazole), we suggest that therapy should be closely monitored. In the case of short-term azole treatment (eg, such as for oral candidiasis), the statin should be stopped or the dose reduced by at least 50% (eg, from 40 or 20 mg to 10 mg).⁶

Prescriber knowledge is sometimes a limiting factor in identifying clinically significant interactions.²² This is especially pertinent in a case like this one, where a lower statin dose may result in a lower chance of the pharmacist alerting the prescribing physician¹⁶ and when an azole is used that is a comparatively weaker CYP450 inhibitor than other azoles such as itraconazole. Even in the era of electronic medical records, approximately 90% of drug interaction alerts are overridden by physicians, and alert fatigue is pronounced.²³

The intricacies and pharmacokinetic principles of this case should contribute to greater provider familiarity with even low-dose simvastatin-fluconazole interactions and help prevent iatrogenic complications such as rhabdomyolysis.

The Advisory Committee on Immunization Practices (ACIP) met 3 times in 2016 and introduced or revised recommendations on influenza, meningococcal, human papillomavirus (HPV), cholera, and hepatitis B vaccines. This Practice Alert highlights the most important new recommendations, except those for influenza vaccines, which were described in a previous Practice Alert.¹ (See the summary of how this year’s flu season compares to last year’s.)

Meningococcal vaccine: Now recommended for HIV-positive patients

Meningococcal conjugate vaccine (serogroups A, C, W, and Y) is recommended for all adolescents ages 11 to 12 as a single dose with a booster at age 16.² It is also recommended for adults and for children (starting at age 2 months) who have high-risk conditions such as functional or anatomic asplenia or complement deficiencies. Others at high risk include microbiologists routinely exposed to isolates of Neisseria meningitidis and those traveling to areas of high meningococcal incidence. ACIP recently added human immunodeficiency virus (HIV) infection to the list of high-risk conditions.³

Two meningococcal conjugate vaccines are available in the United States: Menactra, (Sanofi Pasteur), licensed for use in individuals ages 9 months to 55 years; and Menveo (GlaxoSmithKline), licensed for use in individuals ages 2 months to 55 years. Menveo is the preferred vaccine for children younger than 2 years infected with HIV. However, if Menactra is used, give it at least 4 weeks after completing all pneumococcal conjugate vaccine doses and either before or concomitantly with diphtheria and tetanus toxoid and acellular pertussis vaccine (DTaP). All individuals who are HIV positive should receive a multi-dose primary series and booster doses. The number of primary doses and timing of boosters depends on the product used and the ages of those vaccinated (TABLE³).

Although neither meningococcal conjugate vaccine product is licensed for use in individuals 56 years or older, ACIP recommends using one of the products for HIV-infected individuals in this age group because the only meningococcal vaccine licensed for use in adults 56 or older, meningococcal polysaccharide vaccine (MPSV4, Menomune, Sanofi Pasteur), has not been studied in patients with HIV infection.

Serogroup B. Two vaccine products provide short-term protection against meningococcal serogroup B: MenB-FHbp (Trumenba, Wyeth Pharmaceuticals, Inc.) and MenB-4C (Bexsero, GlaxoSmithKline). In 2015, ACIP made a “B” recommendation for the use of these vaccines in individuals 16 to 23 years of age, with the preferred age range being 16 to 18.⁴ A “B” recommendation means that while ACIP does not advise routine use of the vaccines in this age group, the vaccines can be administered to those who desire them. ACIP has recommended routine use of these products only for individuals 10 years and older who are at high risk for meningococcal disease.⁵

Trumenba was approved as a 3-dose vaccine, administered at 0, 2, and 6 months. Bexsero requires 2 doses given at least one month apart. At its October 2016 meeting, ACIP approved a 2-dose Trumenba schedule, at 0 and 6 months, when administered to those not at risk for meningococcal disease.⁶ However, during an outbreak, and for those at high risk for meningococcal disease, adhere to the original 3-dose schedule.

HPV vaccine: Now a 2-dose schedule for younger patients

The only HPV vaccine available in the United States is the 9-valent HPV vaccine (9vHPV), Gardasil 9. It is approved for both males and females ages 9 to 26 years. ACIP recommends it for both sexes at ages 11 or 12, and advises catch-up doses for men through age 21 and women through age 26. It also recommends vaccination through age 26 for men who have sex with men and men with HIV/acquired immunodeficiency syndrome (AIDS). Children with a history of being sexually abused or assaulted should begin vaccination at age 9 years.

The HPV vaccine is approved for a 3-dose schedule at 0, 1 to 2, and 6 months. At its October 2016 meeting, ACIP approved a 2-dose schedule (0, 6-12 months) for those starting the vaccine before their 15th birthday.⁷ Those starting the vaccine after their 15th birthday, and individuals at any age with an immune-compromising condition, should receive 3 doses. It is hoped that a 2-dose schedule will help to increase the uptake of this safe, effective, and underused vaccine.

Cholera: A new vaccine is available

In June 2016, the FDA approved a live, attenuated, single-dose, oral vaccine (Vaxchora, PaxVax, Inc.) for the prevention of cholera in adults ages 18 to 64 years. It is the only cholera vaccine approved in the United States.

Cholera occurs at low rates among travelers to areas where the disease is endemic. The key to prevention is food and water precautions, and thus the vaccine is not recommended for most travelers—only for those who are at increased risk of exposure to cholera or who have a medical condition that predisposes them to a poor response to medical care if cholera is contracted.⁸ Risk increases with long-term or frequent travel to endemic areas where safe food and water is not always available. Examples of compromising medical conditions include a blood type O, low gastric acidity, and heart or kidney disease.

Duration of the vaccine’s effectiveness is unknown, given a lack of data beyond 6 months. No recommendation for revaccination has been made, and this issue will be assessed as more data are collected. Other unknowns about the vaccine include its effectiveness among immune-suppressed individuals and pregnant women, as well as for those who live in cholera endemic areas or were previously vaccinated with another cholera vaccine.

Hepatitis B: Vaccinate newborns sooner

The incidence of hepatitis B virus (HBV) infection has declined by more than 90% since the introduction of a vaccine in 1982.⁹ However, about 19,000 new cases still arise each year,¹⁰ and about 950 of these are acquired by babies born to HBV-infected mothers.¹¹ About 90% of these infected newborns will develop chronic HBV infection¹² and, if untreated, incur its long-term risks of cirrhosis and liver failure. Hepatitis B vaccine given soon after birth is 75% effective in preventing perinatal HBV infection, and hepatitis B immune globulin (HBIG) is 71% effective.¹³ Used together, the 2 are 94% effective.¹³

Current recommendations for the prevention of HBV include:⁹

• Screen all pregnant women for hepatitis B surface antigen (HBsAg), and use HBIG and hepatitis B vaccines within 12 hours of birth for all newborns whose mothers are HBsAg positive or have an unknown HBsAg status.
• Administer the 3-dose hepatitis B vaccine to all other infants.
• Routinely vaccinate previously unvaccinated children and adolescents.
• Routinely vaccinate adults who are non-immune and at risk for HBV infection.

At its October 2016 meeting, ACIP adopted a comprehensive update of all HBV prevention recommendations. (This will be the subject of a future Practice Alert.) Included was a revision of a previously permissive recommendation that allowed the first dose of hepatitis B vaccine for newborns to be given within 2 months of hospital discharge. The new recommendation⁹ states that newborns of mothers known to be HBsAg negative should be vaccinated within 24 hours (if weight is ≥2000 g) or at age one month or at hospital discharge (if weight is <2000 g).

The first dose should be given within 12 hours of birth to all newborns whose mothers are HBsAg positive or have an unknown HBsAg status.⁹

Immunization schedules

Every year ACIP updates the adult and child immunization schedules to incorporate the changes from the previous year. These can be found on the ACIP Web site at https://www.cdc.gov/vaccines/schedules/hcp/index.html. This Web site remains the most authoritative and accurate source of information on vaccines and immunizations for both professionals and the public.

The Advisory Committee on Immunization Practices (ACIP) met 3 times in 2016 and introduced or revised recommendations on influenza, meningococcal, human papillomavirus (HPV), cholera, and hepatitis B vaccines. This Practice Alert highlights the most important new recommendations, except those for influenza vaccines, which were described in a previous Practice Alert.¹ (See the summary of how this year’s flu season compares to last year’s.)

Meningococcal vaccine: Now recommended for HIV-positive patients

Meningococcal conjugate vaccine (serogroups A, C, W, and Y) is recommended for all adolescents ages 11 to 12 as a single dose with a booster at age 16.² It is also recommended for adults and for children (starting at age 2 months) who have high-risk conditions such as functional or anatomic asplenia or complement deficiencies. Others at high risk include microbiologists routinely exposed to isolates of Neisseria meningitidis and those traveling to areas of high meningococcal incidence. ACIP recently added human immunodeficiency virus (HIV) infection to the list of high-risk conditions.³

Two meningococcal conjugate vaccines are available in the United States: Menactra, (Sanofi Pasteur), licensed for use in individuals ages 9 months to 55 years; and Menveo (GlaxoSmithKline), licensed for use in individuals ages 2 months to 55 years. Menveo is the preferred vaccine for children younger than 2 years infected with HIV. However, if Menactra is used, give it at least 4 weeks after completing all pneumococcal conjugate vaccine doses and either before or concomitantly with diphtheria and tetanus toxoid and acellular pertussis vaccine (DTaP). All individuals who are HIV positive should receive a multi-dose primary series and booster doses. The number of primary doses and timing of boosters depends on the product used and the ages of those vaccinated (TABLE³).

Although neither meningococcal conjugate vaccine product is licensed for use in individuals 56 years or older, ACIP recommends using one of the products for HIV-infected individuals in this age group because the only meningococcal vaccine licensed for use in adults 56 or older, meningococcal polysaccharide vaccine (MPSV4, Menomune, Sanofi Pasteur), has not been studied in patients with HIV infection.

Serogroup B. Two vaccine products provide short-term protection against meningococcal serogroup B: MenB-FHbp (Trumenba, Wyeth Pharmaceuticals, Inc.) and MenB-4C (Bexsero, GlaxoSmithKline). In 2015, ACIP made a “B” recommendation for the use of these vaccines in individuals 16 to 23 years of age, with the preferred age range being 16 to 18.⁴ A “B” recommendation means that while ACIP does not advise routine use of the vaccines in this age group, the vaccines can be administered to those who desire them. ACIP has recommended routine use of these products only for individuals 10 years and older who are at high risk for meningococcal disease.⁵

Trumenba was approved as a 3-dose vaccine, administered at 0, 2, and 6 months. Bexsero requires 2 doses given at least one month apart. At its October 2016 meeting, ACIP approved a 2-dose Trumenba schedule, at 0 and 6 months, when administered to those not at risk for meningococcal disease.⁶ However, during an outbreak, and for those at high risk for meningococcal disease, adhere to the original 3-dose schedule.

HPV vaccine: Now a 2-dose schedule for younger patients

The only HPV vaccine available in the United States is the 9-valent HPV vaccine (9vHPV), Gardasil 9. It is approved for both males and females ages 9 to 26 years. ACIP recommends it for both sexes at ages 11 or 12, and advises catch-up doses for men through age 21 and women through age 26. It also recommends vaccination through age 26 for men who have sex with men and men with HIV/acquired immunodeficiency syndrome (AIDS). Children with a history of being sexually abused or assaulted should begin vaccination at age 9 years.

The HPV vaccine is approved for a 3-dose schedule at 0, 1 to 2, and 6 months. At its October 2016 meeting, ACIP approved a 2-dose schedule (0, 6-12 months) for those starting the vaccine before their 15th birthday.⁷ Those starting the vaccine after their 15th birthday, and individuals at any age with an immune-compromising condition, should receive 3 doses. It is hoped that a 2-dose schedule will help to increase the uptake of this safe, effective, and underused vaccine.

Cholera: A new vaccine is available

In June 2016, the FDA approved a live, attenuated, single-dose, oral vaccine (Vaxchora, PaxVax, Inc.) for the prevention of cholera in adults ages 18 to 64 years. It is the only cholera vaccine approved in the United States.

Cholera occurs at low rates among travelers to areas where the disease is endemic. The key to prevention is food and water precautions, and thus the vaccine is not recommended for most travelers—only for those who are at increased risk of exposure to cholera or who have a medical condition that predisposes them to a poor response to medical care if cholera is contracted.⁸ Risk increases with long-term or frequent travel to endemic areas where safe food and water is not always available. Examples of compromising medical conditions include a blood type O, low gastric acidity, and heart or kidney disease.

Duration of the vaccine’s effectiveness is unknown, given a lack of data beyond 6 months. No recommendation for revaccination has been made, and this issue will be assessed as more data are collected. Other unknowns about the vaccine include its effectiveness among immune-suppressed individuals and pregnant women, as well as for those who live in cholera endemic areas or were previously vaccinated with another cholera vaccine.

Hepatitis B: Vaccinate newborns sooner

The incidence of hepatitis B virus (HBV) infection has declined by more than 90% since the introduction of a vaccine in 1982.⁹ However, about 19,000 new cases still arise each year,¹⁰ and about 950 of these are acquired by babies born to HBV-infected mothers.¹¹ About 90% of these infected newborns will develop chronic HBV infection¹² and, if untreated, incur its long-term risks of cirrhosis and liver failure. Hepatitis B vaccine given soon after birth is 75% effective in preventing perinatal HBV infection, and hepatitis B immune globulin (HBIG) is 71% effective.¹³ Used together, the 2 are 94% effective.¹³

Current recommendations for the prevention of HBV include:⁹

• Screen all pregnant women for hepatitis B surface antigen (HBsAg), and use HBIG and hepatitis B vaccines within 12 hours of birth for all newborns whose mothers are HBsAg positive or have an unknown HBsAg status.
• Administer the 3-dose hepatitis B vaccine to all other infants.
• Routinely vaccinate previously unvaccinated children and adolescents.
• Routinely vaccinate adults who are non-immune and at risk for HBV infection.

At its October 2016 meeting, ACIP adopted a comprehensive update of all HBV prevention recommendations. (This will be the subject of a future Practice Alert.) Included was a revision of a previously permissive recommendation that allowed the first dose of hepatitis B vaccine for newborns to be given within 2 months of hospital discharge. The new recommendation⁹ states that newborns of mothers known to be HBsAg negative should be vaccinated within 24 hours (if weight is ≥2000 g) or at age one month or at hospital discharge (if weight is <2000 g).

The first dose should be given within 12 hours of birth to all newborns whose mothers are HBsAg positive or have an unknown HBsAg status.⁹

Immunization schedules

Every year ACIP updates the adult and child immunization schedules to incorporate the changes from the previous year. These can be found on the ACIP Web site at https://www.cdc.gov/vaccines/schedules/hcp/index.html. This Web site remains the most authoritative and accurate source of information on vaccines and immunizations for both professionals and the public.

The Advisory Committee on Immunization Practices (ACIP) met 3 times in 2016 and introduced or revised recommendations on influenza, meningococcal, human papillomavirus (HPV), cholera, and hepatitis B vaccines. This Practice Alert highlights the most important new recommendations, except those for influenza vaccines, which were described in a previous Practice Alert.¹ (See the summary of how this year’s flu season compares to last year’s.)

Meningococcal vaccine: Now recommended for HIV-positive patients

Meningococcal conjugate vaccine (serogroups A, C, W, and Y) is recommended for all adolescents ages 11 to 12 as a single dose with a booster at age 16.² It is also recommended for adults and for children (starting at age 2 months) who have high-risk conditions such as functional or anatomic asplenia or complement deficiencies. Others at high risk include microbiologists routinely exposed to isolates of Neisseria meningitidis and those traveling to areas of high meningococcal incidence. ACIP recently added human immunodeficiency virus (HIV) infection to the list of high-risk conditions.³

Two meningococcal conjugate vaccines are available in the United States: Menactra, (Sanofi Pasteur), licensed for use in individuals ages 9 months to 55 years; and Menveo (GlaxoSmithKline), licensed for use in individuals ages 2 months to 55 years. Menveo is the preferred vaccine for children younger than 2 years infected with HIV. However, if Menactra is used, give it at least 4 weeks after completing all pneumococcal conjugate vaccine doses and either before or concomitantly with diphtheria and tetanus toxoid and acellular pertussis vaccine (DTaP). All individuals who are HIV positive should receive a multi-dose primary series and booster doses. The number of primary doses and timing of boosters depends on the product used and the ages of those vaccinated (TABLE³).

Although neither meningococcal conjugate vaccine product is licensed for use in individuals 56 years or older, ACIP recommends using one of the products for HIV-infected individuals in this age group because the only meningococcal vaccine licensed for use in adults 56 or older, meningococcal polysaccharide vaccine (MPSV4, Menomune, Sanofi Pasteur), has not been studied in patients with HIV infection.

Serogroup B. Two vaccine products provide short-term protection against meningococcal serogroup B: MenB-FHbp (Trumenba, Wyeth Pharmaceuticals, Inc.) and MenB-4C (Bexsero, GlaxoSmithKline). In 2015, ACIP made a “B” recommendation for the use of these vaccines in individuals 16 to 23 years of age, with the preferred age range being 16 to 18.⁴ A “B” recommendation means that while ACIP does not advise routine use of the vaccines in this age group, the vaccines can be administered to those who desire them. ACIP has recommended routine use of these products only for individuals 10 years and older who are at high risk for meningococcal disease.⁵

Trumenba was approved as a 3-dose vaccine, administered at 0, 2, and 6 months. Bexsero requires 2 doses given at least one month apart. At its October 2016 meeting, ACIP approved a 2-dose Trumenba schedule, at 0 and 6 months, when administered to those not at risk for meningococcal disease.⁶ However, during an outbreak, and for those at high risk for meningococcal disease, adhere to the original 3-dose schedule.

HPV vaccine: Now a 2-dose schedule for younger patients

The only HPV vaccine available in the United States is the 9-valent HPV vaccine (9vHPV), Gardasil 9. It is approved for both males and females ages 9 to 26 years. ACIP recommends it for both sexes at ages 11 or 12, and advises catch-up doses for men through age 21 and women through age 26. It also recommends vaccination through age 26 for men who have sex with men and men with HIV/acquired immunodeficiency syndrome (AIDS). Children with a history of being sexually abused or assaulted should begin vaccination at age 9 years.

The HPV vaccine is approved for a 3-dose schedule at 0, 1 to 2, and 6 months. At its October 2016 meeting, ACIP approved a 2-dose schedule (0, 6-12 months) for those starting the vaccine before their 15th birthday.⁷ Those starting the vaccine after their 15th birthday, and individuals at any age with an immune-compromising condition, should receive 3 doses. It is hoped that a 2-dose schedule will help to increase the uptake of this safe, effective, and underused vaccine.

Cholera: A new vaccine is available

In June 2016, the FDA approved a live, attenuated, single-dose, oral vaccine (Vaxchora, PaxVax, Inc.) for the prevention of cholera in adults ages 18 to 64 years. It is the only cholera vaccine approved in the United States.

Cholera occurs at low rates among travelers to areas where the disease is endemic. The key to prevention is food and water precautions, and thus the vaccine is not recommended for most travelers—only for those who are at increased risk of exposure to cholera or who have a medical condition that predisposes them to a poor response to medical care if cholera is contracted.⁸ Risk increases with long-term or frequent travel to endemic areas where safe food and water is not always available. Examples of compromising medical conditions include a blood type O, low gastric acidity, and heart or kidney disease.

Duration of the vaccine’s effectiveness is unknown, given a lack of data beyond 6 months. No recommendation for revaccination has been made, and this issue will be assessed as more data are collected. Other unknowns about the vaccine include its effectiveness among immune-suppressed individuals and pregnant women, as well as for those who live in cholera endemic areas or were previously vaccinated with another cholera vaccine.

Hepatitis B: Vaccinate newborns sooner

The incidence of hepatitis B virus (HBV) infection has declined by more than 90% since the introduction of a vaccine in 1982.⁹ However, about 19,000 new cases still arise each year,¹⁰ and about 950 of these are acquired by babies born to HBV-infected mothers.¹¹ About 90% of these infected newborns will develop chronic HBV infection¹² and, if untreated, incur its long-term risks of cirrhosis and liver failure. Hepatitis B vaccine given soon after birth is 75% effective in preventing perinatal HBV infection, and hepatitis B immune globulin (HBIG) is 71% effective.¹³ Used together, the 2 are 94% effective.¹³

Current recommendations for the prevention of HBV include:⁹

• Screen all pregnant women for hepatitis B surface antigen (HBsAg), and use HBIG and hepatitis B vaccines within 12 hours of birth for all newborns whose mothers are HBsAg positive or have an unknown HBsAg status.
• Administer the 3-dose hepatitis B vaccine to all other infants.
• Routinely vaccinate previously unvaccinated children and adolescents.
• Routinely vaccinate adults who are non-immune and at risk for HBV infection.

At its October 2016 meeting, ACIP adopted a comprehensive update of all HBV prevention recommendations. (This will be the subject of a future Practice Alert.) Included was a revision of a previously permissive recommendation that allowed the first dose of hepatitis B vaccine for newborns to be given within 2 months of hospital discharge. The new recommendation⁹ states that newborns of mothers known to be HBsAg negative should be vaccinated within 24 hours (if weight is ≥2000 g) or at age one month or at hospital discharge (if weight is <2000 g).

The first dose should be given within 12 hours of birth to all newborns whose mothers are HBsAg positive or have an unknown HBsAg status.⁹

Immunization schedules

Every year ACIP updates the adult and child immunization schedules to incorporate the changes from the previous year. These can be found on the ACIP Web site at https://www.cdc.gov/vaccines/schedules/hcp/index.html. This Web site remains the most authoritative and accurate source of information on vaccines and immunizations for both professionals and the public.

CASE › A 52-year-old right-hand-dominant white man arrived at our clinic complaining that he was unable to straighten his right ring finger. He had no associated pain or numbness, and had not injured his hand. The patient had type 2 diabetes that was controlled with metformin. He had no history of surgery or drug allergies, did not smoke, and said he drank 2 to 3 alcoholic beverages per day. He was a car salesman and was self-conscious when shaking hands with customers. On physical examination, we noted that he held his right ring finger at roughly 45 degrees of flexion at the metacarpophalangeal joint; a painless cord-like structure was palpable on the palmar surface of that joint. His left hand had no abnormalities.

If this were your patient, how would you proceed?

Dupuytren’s disease (DD) is a disabling fibroproliferative disorder of the hand for which there is no cure. While the exact cause of DD is unknown, it has been linked to a number of risk factors, including smoking, alcohol consumption, and diabetes. It affects about 5% of the US population, and up to 70% of affected individuals may initially seek treatment from a primary care physician.¹ The disease is also referred to as Dupuytren’s contracture, which describes the flexion contractures of fingers at the end stage of the disease. Palmar fibromatosis is yet another name for the disorder.

DD refers to a spectrum of presentations ranging from nodules to cords to discernible contractures, and it is not known which patients with early Dupuytren changes will progress to severe contracture. With recognition of early changes, nonsurgical intervention is possible, such as collagenase injection or percutaneous fasciotomy, and can slow the progression of DD, restore function, and avoid or delay surgical intervention. DD is a clinically challenging disorder. Treatment for an affected area may resolve symptoms, only to have them recur in that location or another.

How underlying pathology correlates with clinical findings

DD affects the palmar fascia, a thick triangular-shaped sheet of dense fibrous collagenous connective tissue that lies deep to the dermis and superficial to the flexor tendons of the hand with fibers extending both into the skin and into the deep tissue. The palmar fascia secures the skin during gripping and twisting motions, and it bifurcates into distal extensions, called pretendinous bands, that overlay and mimic the flexor tendons.

Clinical findings reflect the progression of underlying pathology. The earliest manifestation of DD is painless dimpling of the skin on the palmar surface of the hand.² Over time, the underlying fibrosis with increased collagen deposition can progress, leading to development of nodules and eventually, cords, which are sometimes mistaken for flexor tendons. Dupuytren-like fibrotic tissue can occur on the sole of the foot (Ledderhose disease) and penis (Peyronie’s disease).^2,3 In patients with these coexisting conditions, prognosis is generally worse.⁴ With the hands, bilateral involvement is common, although it is usually more severe in one hand. The ring finger is the digit most frequently involved, followed by the little finger, middle finger, and index finger. The thumb is rarely affected.³

As the disease progresses and cords contract, the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints develop flexion contractures. The distal interphalangeal (DIP) joint, rarely involved, instead exhibits a hyperextension contracture. Digital flexion contractures are often disabling, interfering with daily activities such as picking up a glass, shaking hands, or putting one's hand in a pants pocket. Many patients seek medical attention only after a palpable nodule, cord, or flexion contracture becomes apparent (FIGURE 1).

In a study of 326 patients who reported Dupuytren’s symptoms, the most common symptoms that led them to seek treatment were, in descending order, a hard bump (48%), a ropelike growth (12%), dimpling (11%), and finger contractures (10%). Only 9% of patients seeking treatment for hand symptoms associated with DD had received a diagnosis of DD from their initial medical encounter, causing an unnecessary delay in treatment.¹

Who is at increased risk for DD?

DD is most often seen in elderly white men of European descent.⁵ In the United States, the prevalence of the disease is roughly 5%,¹ compared with 4% to 39% in northwestern Europe (eg, Iceland).⁶ The male-to-female ratio of DD ranges from 6:1 to 15:1.⁷ The prevalence of DD appears to increase with age. The prevalence in men and women is similar up to age 45 years, after which the rate is much greater in males.⁷

DD is associated with many risk factors including smoking, alcohol consumption, vascular insufficiency, epilepsy, hyperlipidemia, manual labor, occupations with exposure to vibration, hand trauma, and even hand surgery such as carpal tunnel release or trigger finger release.^8-11 It is also associated with diabetes; particularly type 1 insulin-dependent diabetes.¹² There may also be an association with frozen shoulder.^12,13

The need for surgical treatment of DD becomes more likely with a history of cigarette smoking and heavy alcohol consumption. There seems to be an association with epilepsy, most likely from anti-epileptic drugs.¹⁴ Rheumatoid arthritis is the only condition that has been associated with a lower incidence of DD, possibly because of the use of anti-inflammatory drugs.¹⁵ There are genetic differences between patients with and without DD, although a “Dupuytren’s gene” has not been identified.

Rule out possible DD mimics

The differential diagnosis for flexion contracture of the MCP or PIP joints seen in Dupuytren’s disease includes stenosing flexor tenosynovitis, or trigger finger. Other conditions that can mimic DD are ulnar claw hand, trauma scars, intrinsic joint diseases such as degenerative or rheumatoid arthritis (RA), diabetic cheiroarthropathy, camptodactyly, and Volkmann’s contracture. Trauma scars—especially longitudinal scars—have a tendency to contract and develop keloid formation.

It's not known which patients with early Dupuytren changes will progress to severe contracture.

Stenosing flexor tenosynovitis and ulnar claw hand are distinguishable from DD by full or nearly full active or passive extension of the affected digit, whereas DD is a true contracture of the joint that does not allow full extension. A careful history can rule out previous injury to the area. Although intrinsic joint disease, such as RA, can cause finger contractures, the joints are usually enlarged, painful, and associated with characteristic radiologic findings.

Unlike DD, diabetic cheiroarthropathy often involves all of the digits except for the thumb, and is often associated with a waxy appearance of the skin. Camptodactyly is an autosomal dominant disorder that more often presents in childhood and can be caused by a number of congenital syndromes. Volkmann’s contracture can manifest as a claw-like deformity of the hand caused by undiagnosed compartment syndrome of the forearm.

Assess the severity of DD

In your evaluation, first identify palmar or digital fibromatosis presenting as a nodule or a cord. Second, estimate the degree of MCP and PIP joint contractures. A common measure of contracture is the Hueston tabletop test. Ask the patient to place the palm of the hand on a flat surface. If the patient is unable to completely flatten the hand against the surface, presume a positive result (FIGURE 2).¹⁶

An accurate measure of the degree of flexion can be accomplished with a goniometer. For a simple assessment of severity, have the patient place each affected finger along the convexity of a spoon. If adjoining surfaces are flush, assume that the contracture is at least 30 degrees (FIGURE 3). The severity of DD can also be graded according to the Tubiana classification system (TABLE¹⁷), wherein the total deformity or contracture score is the sum of the angles of all 3 digital joints of the finger.

A look at the treatment options

Once the diagnosis of DD is made, reassure the patient that the disease is not cancerous, although it may be progressive. Advise patients, too, that several treatment options (detailed below) are available, but that surgery is the mainstay of treatment. (Of note: Despite what would seem logical, stretching a cord to straighten the finger is not recommended, as it may actually worsen the condition.¹⁸)

Options for early DD. Corticosteroids such as triamcinolone may have a role as an adjunct for early DD by reducing the size and firmness of the Dupuytren’s nodules and possibly slowing the progression of the disease. However, in one study of 63 patients, half of the individuals experienced reactivation of disease between one and 3 years.¹⁹

Radiotherapy has been studied as a potential treatment for early DD and for patients unable to undergo surgery. Radiation does have a biologic effect on nodular DD, but has no effect on the cords that cause the joint contracture. In a long-term follow-up study of 135 patients treated with radiotherapy, disease remained stable in 59% of patients, improved in 10%, and progressed in 31%.²⁰ Results were better for early stage disease. This modality is not used for more advanced cases.

Surgery is the primary method by which to restore function and minimize complications. In the past, referral was recom­mended for MCP joint contractures >30 degrees or for any involvment of the PIP joint, because involvement of the latter carries a worse prognosis and may not be fully correctable, even with surgery.²¹ However, treatment may also be warranted in cases of functional disability—regardless of the degree of contracture (eg, for pain associated with a prominent nodule or cord when gripping objects).

Although fasciectomies have shown the best efficacy and lowest recurrence rates, complications are more likely with these procedures.Depending on disease progression and the surgeon’s preference, the most popular procedures are fasciotomies and fasciectomies. Surgical options for contractures—in increasing order of invasiveness and amounts of fascia removed—are fasciotomy (needle, open), fasciectomy (partial, radical), and dermofasciectomy.

Needle fasciotomy is an outpatient procedure performed under local block. The surgeon uses a needle bevel to transect the diseased cord at multiple puncture sites.

Open fasciotomy is also an outpatient procedure involving an incision that allows direct visualization of the cord and internal structures before dividing the fascia. Percutaneous and open fasciotomies are more successful for MCP joint contractures and less successful for PIP joint contractures.

With partial fasciectomy, only the grossly affected fascia is removed.

With radical fasciectomy, the entire palmar fascia is removed, regardless of which areas are grossly diseased.

Dermofasciectomy removes diseased fascia and the overlying skin, with a skin graft applied to heal the wound.

Another option: Collagenase injection. In February 2010, the US Food and Drug Administration approved collagenase clostridium histolyticum (Xiaflex) as the first drug specifically indicated for the treatment of Dupuytren’s contracture. Collagenase is injected directly into the fascial cord, cleaving its collagen component and progressively softening and breaking down the cord. If not properly injected, collagenase may injure neurovascular structures and may rupture tendons.

So how do the treatment options compare?

We found no randomized prospective trials comparing treatment options for DD, but there are a number of trials that shed light on a variety of the available options.

Treatment success. In general, partial fasciectomies have shown the greatest success in reducing contractures and maintaining the lowest recurrence rates. Correction of contracture to ≤5 degrees was seen in 94% of MCP joint contractures treated with partial fasciectomy, in 77% of MCP joints treated with collagenase, and in 55% of MCP joints treated with percutaneous needle fasciotomies.^22,23 PIP joint contracture correction was not as successful: Correction of contracture to ≤5 degrees was seen in 47% of those treated with partial fasciectomy, 40% treated with collagenase, and 26% treated with needle fasciotomy.^22,23

Recurrence rates. When recurrence was defined as loss of passive extension >30 degrees, the recurrence rate for MCP joint contractures with partial fasciectomy was 21%, compared with 85% for needle fasciotomy.²² In a similar review, recurrence rates for partial fasciectomy ranged from 12% to 39% compared with 50% to 58% for needle fasciotomy.²⁴ With collagenase injection, 5-year data have shown an overall recurrence rate of 32%, with a recurrence of 26% at the MCP joint and 46% at the PIP joint.²⁵ In this trial, recurrence was defined as more than 30% worsening of flexion.²⁵

Complications. Although fasciectomies have shown the best efficacy and lowest recurrence rates, complications such as infection, neurapraxia, and digital nerve injury are more likely with these procedures.^26,27

Early recognition and referral to a hand specialist for the treatment of DD may allow the use of less invasive techniques and improved functional results.

CASE › Absent a history of trauma and features typical of other hand/digit disorders, we diagnosed Dupuytren’s disease in this patient. Potential treatments included partial fasciectomy and collagenase injection. After discussing the risks and benefits of each of these procedures, the patient elected to undergo a partial fasciectomy. The surgery was uncomplicated and the abnormality was corrected to within 5 degrees of full extension. At the patient’s one-year follow-up visit, there was no evidence of recurrence.

CASE › A 52-year-old right-hand-dominant white man arrived at our clinic complaining that he was unable to straighten his right ring finger. He had no associated pain or numbness, and had not injured his hand. The patient had type 2 diabetes that was controlled with metformin. He had no history of surgery or drug allergies, did not smoke, and said he drank 2 to 3 alcoholic beverages per day. He was a car salesman and was self-conscious when shaking hands with customers. On physical examination, we noted that he held his right ring finger at roughly 45 degrees of flexion at the metacarpophalangeal joint; a painless cord-like structure was palpable on the palmar surface of that joint. His left hand had no abnormalities.

If this were your patient, how would you proceed?

Dupuytren’s disease (DD) is a disabling fibroproliferative disorder of the hand for which there is no cure. While the exact cause of DD is unknown, it has been linked to a number of risk factors, including smoking, alcohol consumption, and diabetes. It affects about 5% of the US population, and up to 70% of affected individuals may initially seek treatment from a primary care physician.¹ The disease is also referred to as Dupuytren’s contracture, which describes the flexion contractures of fingers at the end stage of the disease. Palmar fibromatosis is yet another name for the disorder.

DD refers to a spectrum of presentations ranging from nodules to cords to discernible contractures, and it is not known which patients with early Dupuytren changes will progress to severe contracture. With recognition of early changes, nonsurgical intervention is possible, such as collagenase injection or percutaneous fasciotomy, and can slow the progression of DD, restore function, and avoid or delay surgical intervention. DD is a clinically challenging disorder. Treatment for an affected area may resolve symptoms, only to have them recur in that location or another.

How underlying pathology correlates with clinical findings

DD affects the palmar fascia, a thick triangular-shaped sheet of dense fibrous collagenous connective tissue that lies deep to the dermis and superficial to the flexor tendons of the hand with fibers extending both into the skin and into the deep tissue. The palmar fascia secures the skin during gripping and twisting motions, and it bifurcates into distal extensions, called pretendinous bands, that overlay and mimic the flexor tendons.

Clinical findings reflect the progression of underlying pathology. The earliest manifestation of DD is painless dimpling of the skin on the palmar surface of the hand.² Over time, the underlying fibrosis with increased collagen deposition can progress, leading to development of nodules and eventually, cords, which are sometimes mistaken for flexor tendons. Dupuytren-like fibrotic tissue can occur on the sole of the foot (Ledderhose disease) and penis (Peyronie’s disease).^2,3 In patients with these coexisting conditions, prognosis is generally worse.⁴ With the hands, bilateral involvement is common, although it is usually more severe in one hand. The ring finger is the digit most frequently involved, followed by the little finger, middle finger, and index finger. The thumb is rarely affected.³

As the disease progresses and cords contract, the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints develop flexion contractures. The distal interphalangeal (DIP) joint, rarely involved, instead exhibits a hyperextension contracture. Digital flexion contractures are often disabling, interfering with daily activities such as picking up a glass, shaking hands, or putting one's hand in a pants pocket. Many patients seek medical attention only after a palpable nodule, cord, or flexion contracture becomes apparent (FIGURE 1).

In a study of 326 patients who reported Dupuytren’s symptoms, the most common symptoms that led them to seek treatment were, in descending order, a hard bump (48%), a ropelike growth (12%), dimpling (11%), and finger contractures (10%). Only 9% of patients seeking treatment for hand symptoms associated with DD had received a diagnosis of DD from their initial medical encounter, causing an unnecessary delay in treatment.¹

Who is at increased risk for DD?

DD is most often seen in elderly white men of European descent.⁵ In the United States, the prevalence of the disease is roughly 5%,¹ compared with 4% to 39% in northwestern Europe (eg, Iceland).⁶ The male-to-female ratio of DD ranges from 6:1 to 15:1.⁷ The prevalence of DD appears to increase with age. The prevalence in men and women is similar up to age 45 years, after which the rate is much greater in males.⁷

DD is associated with many risk factors including smoking, alcohol consumption, vascular insufficiency, epilepsy, hyperlipidemia, manual labor, occupations with exposure to vibration, hand trauma, and even hand surgery such as carpal tunnel release or trigger finger release.^8-11 It is also associated with diabetes; particularly type 1 insulin-dependent diabetes.¹² There may also be an association with frozen shoulder.^12,13

The need for surgical treatment of DD becomes more likely with a history of cigarette smoking and heavy alcohol consumption. There seems to be an association with epilepsy, most likely from anti-epileptic drugs.¹⁴ Rheumatoid arthritis is the only condition that has been associated with a lower incidence of DD, possibly because of the use of anti-inflammatory drugs.¹⁵ There are genetic differences between patients with and without DD, although a “Dupuytren’s gene” has not been identified.

Rule out possible DD mimics

The differential diagnosis for flexion contracture of the MCP or PIP joints seen in Dupuytren’s disease includes stenosing flexor tenosynovitis, or trigger finger. Other conditions that can mimic DD are ulnar claw hand, trauma scars, intrinsic joint diseases such as degenerative or rheumatoid arthritis (RA), diabetic cheiroarthropathy, camptodactyly, and Volkmann’s contracture. Trauma scars—especially longitudinal scars—have a tendency to contract and develop keloid formation.

It's not known which patients with early Dupuytren changes will progress to severe contracture.

Stenosing flexor tenosynovitis and ulnar claw hand are distinguishable from DD by full or nearly full active or passive extension of the affected digit, whereas DD is a true contracture of the joint that does not allow full extension. A careful history can rule out previous injury to the area. Although intrinsic joint disease, such as RA, can cause finger contractures, the joints are usually enlarged, painful, and associated with characteristic radiologic findings.

Unlike DD, diabetic cheiroarthropathy often involves all of the digits except for the thumb, and is often associated with a waxy appearance of the skin. Camptodactyly is an autosomal dominant disorder that more often presents in childhood and can be caused by a number of congenital syndromes. Volkmann’s contracture can manifest as a claw-like deformity of the hand caused by undiagnosed compartment syndrome of the forearm.

Assess the severity of DD

In your evaluation, first identify palmar or digital fibromatosis presenting as a nodule or a cord. Second, estimate the degree of MCP and PIP joint contractures. A common measure of contracture is the Hueston tabletop test. Ask the patient to place the palm of the hand on a flat surface. If the patient is unable to completely flatten the hand against the surface, presume a positive result (FIGURE 2).¹⁶

An accurate measure of the degree of flexion can be accomplished with a goniometer. For a simple assessment of severity, have the patient place each affected finger along the convexity of a spoon. If adjoining surfaces are flush, assume that the contracture is at least 30 degrees (FIGURE 3). The severity of DD can also be graded according to the Tubiana classification system (TABLE¹⁷), wherein the total deformity or contracture score is the sum of the angles of all 3 digital joints of the finger.

A look at the treatment options

Once the diagnosis of DD is made, reassure the patient that the disease is not cancerous, although it may be progressive. Advise patients, too, that several treatment options (detailed below) are available, but that surgery is the mainstay of treatment. (Of note: Despite what would seem logical, stretching a cord to straighten the finger is not recommended, as it may actually worsen the condition.¹⁸)

Options for early DD. Corticosteroids such as triamcinolone may have a role as an adjunct for early DD by reducing the size and firmness of the Dupuytren’s nodules and possibly slowing the progression of the disease. However, in one study of 63 patients, half of the individuals experienced reactivation of disease between one and 3 years.¹⁹

Radiotherapy has been studied as a potential treatment for early DD and for patients unable to undergo surgery. Radiation does have a biologic effect on nodular DD, but has no effect on the cords that cause the joint contracture. In a long-term follow-up study of 135 patients treated with radiotherapy, disease remained stable in 59% of patients, improved in 10%, and progressed in 31%.²⁰ Results were better for early stage disease. This modality is not used for more advanced cases.

Surgery is the primary method by which to restore function and minimize complications. In the past, referral was recom­mended for MCP joint contractures >30 degrees or for any involvment of the PIP joint, because involvement of the latter carries a worse prognosis and may not be fully correctable, even with surgery.²¹ However, treatment may also be warranted in cases of functional disability—regardless of the degree of contracture (eg, for pain associated with a prominent nodule or cord when gripping objects).

Although fasciectomies have shown the best efficacy and lowest recurrence rates, complications are more likely with these procedures.Depending on disease progression and the surgeon’s preference, the most popular procedures are fasciotomies and fasciectomies. Surgical options for contractures—in increasing order of invasiveness and amounts of fascia removed—are fasciotomy (needle, open), fasciectomy (partial, radical), and dermofasciectomy.

Needle fasciotomy is an outpatient procedure performed under local block. The surgeon uses a needle bevel to transect the diseased cord at multiple puncture sites.

Open fasciotomy is also an outpatient procedure involving an incision that allows direct visualization of the cord and internal structures before dividing the fascia. Percutaneous and open fasciotomies are more successful for MCP joint contractures and less successful for PIP joint contractures.

With partial fasciectomy, only the grossly affected fascia is removed.

With radical fasciectomy, the entire palmar fascia is removed, regardless of which areas are grossly diseased.

Dermofasciectomy removes diseased fascia and the overlying skin, with a skin graft applied to heal the wound.

Another option: Collagenase injection. In February 2010, the US Food and Drug Administration approved collagenase clostridium histolyticum (Xiaflex) as the first drug specifically indicated for the treatment of Dupuytren’s contracture. Collagenase is injected directly into the fascial cord, cleaving its collagen component and progressively softening and breaking down the cord. If not properly injected, collagenase may injure neurovascular structures and may rupture tendons.

So how do the treatment options compare?

We found no randomized prospective trials comparing treatment options for DD, but there are a number of trials that shed light on a variety of the available options.

Treatment success. In general, partial fasciectomies have shown the greatest success in reducing contractures and maintaining the lowest recurrence rates. Correction of contracture to ≤5 degrees was seen in 94% of MCP joint contractures treated with partial fasciectomy, in 77% of MCP joints treated with collagenase, and in 55% of MCP joints treated with percutaneous needle fasciotomies.^22,23 PIP joint contracture correction was not as successful: Correction of contracture to ≤5 degrees was seen in 47% of those treated with partial fasciectomy, 40% treated with collagenase, and 26% treated with needle fasciotomy.^22,23

Recurrence rates. When recurrence was defined as loss of passive extension >30 degrees, the recurrence rate for MCP joint contractures with partial fasciectomy was 21%, compared with 85% for needle fasciotomy.²² In a similar review, recurrence rates for partial fasciectomy ranged from 12% to 39% compared with 50% to 58% for needle fasciotomy.²⁴ With collagenase injection, 5-year data have shown an overall recurrence rate of 32%, with a recurrence of 26% at the MCP joint and 46% at the PIP joint.²⁵ In this trial, recurrence was defined as more than 30% worsening of flexion.²⁵

Complications. Although fasciectomies have shown the best efficacy and lowest recurrence rates, complications such as infection, neurapraxia, and digital nerve injury are more likely with these procedures.^26,27

Early recognition and referral to a hand specialist for the treatment of DD may allow the use of less invasive techniques and improved functional results.

CASE › Absent a history of trauma and features typical of other hand/digit disorders, we diagnosed Dupuytren’s disease in this patient. Potential treatments included partial fasciectomy and collagenase injection. After discussing the risks and benefits of each of these procedures, the patient elected to undergo a partial fasciectomy. The surgery was uncomplicated and the abnormality was corrected to within 5 degrees of full extension. At the patient’s one-year follow-up visit, there was no evidence of recurrence.

CASE › A 52-year-old right-hand-dominant white man arrived at our clinic complaining that he was unable to straighten his right ring finger. He had no associated pain or numbness, and had not injured his hand. The patient had type 2 diabetes that was controlled with metformin. He had no history of surgery or drug allergies, did not smoke, and said he drank 2 to 3 alcoholic beverages per day. He was a car salesman and was self-conscious when shaking hands with customers. On physical examination, we noted that he held his right ring finger at roughly 45 degrees of flexion at the metacarpophalangeal joint; a painless cord-like structure was palpable on the palmar surface of that joint. His left hand had no abnormalities.

If this were your patient, how would you proceed?

Dupuytren’s disease (DD) is a disabling fibroproliferative disorder of the hand for which there is no cure. While the exact cause of DD is unknown, it has been linked to a number of risk factors, including smoking, alcohol consumption, and diabetes. It affects about 5% of the US population, and up to 70% of affected individuals may initially seek treatment from a primary care physician.¹ The disease is also referred to as Dupuytren’s contracture, which describes the flexion contractures of fingers at the end stage of the disease. Palmar fibromatosis is yet another name for the disorder.

DD refers to a spectrum of presentations ranging from nodules to cords to discernible contractures, and it is not known which patients with early Dupuytren changes will progress to severe contracture. With recognition of early changes, nonsurgical intervention is possible, such as collagenase injection or percutaneous fasciotomy, and can slow the progression of DD, restore function, and avoid or delay surgical intervention. DD is a clinically challenging disorder. Treatment for an affected area may resolve symptoms, only to have them recur in that location or another.

How underlying pathology correlates with clinical findings

DD affects the palmar fascia, a thick triangular-shaped sheet of dense fibrous collagenous connective tissue that lies deep to the dermis and superficial to the flexor tendons of the hand with fibers extending both into the skin and into the deep tissue. The palmar fascia secures the skin during gripping and twisting motions, and it bifurcates into distal extensions, called pretendinous bands, that overlay and mimic the flexor tendons.

Clinical findings reflect the progression of underlying pathology. The earliest manifestation of DD is painless dimpling of the skin on the palmar surface of the hand.² Over time, the underlying fibrosis with increased collagen deposition can progress, leading to development of nodules and eventually, cords, which are sometimes mistaken for flexor tendons. Dupuytren-like fibrotic tissue can occur on the sole of the foot (Ledderhose disease) and penis (Peyronie’s disease).^2,3 In patients with these coexisting conditions, prognosis is generally worse.⁴ With the hands, bilateral involvement is common, although it is usually more severe in one hand. The ring finger is the digit most frequently involved, followed by the little finger, middle finger, and index finger. The thumb is rarely affected.³

As the disease progresses and cords contract, the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints develop flexion contractures. The distal interphalangeal (DIP) joint, rarely involved, instead exhibits a hyperextension contracture. Digital flexion contractures are often disabling, interfering with daily activities such as picking up a glass, shaking hands, or putting one's hand in a pants pocket. Many patients seek medical attention only after a palpable nodule, cord, or flexion contracture becomes apparent (FIGURE 1).

In a study of 326 patients who reported Dupuytren’s symptoms, the most common symptoms that led them to seek treatment were, in descending order, a hard bump (48%), a ropelike growth (12%), dimpling (11%), and finger contractures (10%). Only 9% of patients seeking treatment for hand symptoms associated with DD had received a diagnosis of DD from their initial medical encounter, causing an unnecessary delay in treatment.¹

Who is at increased risk for DD?

DD is most often seen in elderly white men of European descent.⁵ In the United States, the prevalence of the disease is roughly 5%,¹ compared with 4% to 39% in northwestern Europe (eg, Iceland).⁶ The male-to-female ratio of DD ranges from 6:1 to 15:1.⁷ The prevalence of DD appears to increase with age. The prevalence in men and women is similar up to age 45 years, after which the rate is much greater in males.⁷

DD is associated with many risk factors including smoking, alcohol consumption, vascular insufficiency, epilepsy, hyperlipidemia, manual labor, occupations with exposure to vibration, hand trauma, and even hand surgery such as carpal tunnel release or trigger finger release.^8-11 It is also associated with diabetes; particularly type 1 insulin-dependent diabetes.¹² There may also be an association with frozen shoulder.^12,13

The need for surgical treatment of DD becomes more likely with a history of cigarette smoking and heavy alcohol consumption. There seems to be an association with epilepsy, most likely from anti-epileptic drugs.¹⁴ Rheumatoid arthritis is the only condition that has been associated with a lower incidence of DD, possibly because of the use of anti-inflammatory drugs.¹⁵ There are genetic differences between patients with and without DD, although a “Dupuytren’s gene” has not been identified.

Rule out possible DD mimics

The differential diagnosis for flexion contracture of the MCP or PIP joints seen in Dupuytren’s disease includes stenosing flexor tenosynovitis, or trigger finger. Other conditions that can mimic DD are ulnar claw hand, trauma scars, intrinsic joint diseases such as degenerative or rheumatoid arthritis (RA), diabetic cheiroarthropathy, camptodactyly, and Volkmann’s contracture. Trauma scars—especially longitudinal scars—have a tendency to contract and develop keloid formation.

It's not known which patients with early Dupuytren changes will progress to severe contracture.

Stenosing flexor tenosynovitis and ulnar claw hand are distinguishable from DD by full or nearly full active or passive extension of the affected digit, whereas DD is a true contracture of the joint that does not allow full extension. A careful history can rule out previous injury to the area. Although intrinsic joint disease, such as RA, can cause finger contractures, the joints are usually enlarged, painful, and associated with characteristic radiologic findings.

Unlike DD, diabetic cheiroarthropathy often involves all of the digits except for the thumb, and is often associated with a waxy appearance of the skin. Camptodactyly is an autosomal dominant disorder that more often presents in childhood and can be caused by a number of congenital syndromes. Volkmann’s contracture can manifest as a claw-like deformity of the hand caused by undiagnosed compartment syndrome of the forearm.

Assess the severity of DD

In your evaluation, first identify palmar or digital fibromatosis presenting as a nodule or a cord. Second, estimate the degree of MCP and PIP joint contractures. A common measure of contracture is the Hueston tabletop test. Ask the patient to place the palm of the hand on a flat surface. If the patient is unable to completely flatten the hand against the surface, presume a positive result (FIGURE 2).¹⁶

An accurate measure of the degree of flexion can be accomplished with a goniometer. For a simple assessment of severity, have the patient place each affected finger along the convexity of a spoon. If adjoining surfaces are flush, assume that the contracture is at least 30 degrees (FIGURE 3). The severity of DD can also be graded according to the Tubiana classification system (TABLE¹⁷), wherein the total deformity or contracture score is the sum of the angles of all 3 digital joints of the finger.

A look at the treatment options

Once the diagnosis of DD is made, reassure the patient that the disease is not cancerous, although it may be progressive. Advise patients, too, that several treatment options (detailed below) are available, but that surgery is the mainstay of treatment. (Of note: Despite what would seem logical, stretching a cord to straighten the finger is not recommended, as it may actually worsen the condition.¹⁸)

Options for early DD. Corticosteroids such as triamcinolone may have a role as an adjunct for early DD by reducing the size and firmness of the Dupuytren’s nodules and possibly slowing the progression of the disease. However, in one study of 63 patients, half of the individuals experienced reactivation of disease between one and 3 years.¹⁹

Radiotherapy has been studied as a potential treatment for early DD and for patients unable to undergo surgery. Radiation does have a biologic effect on nodular DD, but has no effect on the cords that cause the joint contracture. In a long-term follow-up study of 135 patients treated with radiotherapy, disease remained stable in 59% of patients, improved in 10%, and progressed in 31%.²⁰ Results were better for early stage disease. This modality is not used for more advanced cases.

Surgery is the primary method by which to restore function and minimize complications. In the past, referral was recom­mended for MCP joint contractures >30 degrees or for any involvment of the PIP joint, because involvement of the latter carries a worse prognosis and may not be fully correctable, even with surgery.²¹ However, treatment may also be warranted in cases of functional disability—regardless of the degree of contracture (eg, for pain associated with a prominent nodule or cord when gripping objects).

Although fasciectomies have shown the best efficacy and lowest recurrence rates, complications are more likely with these procedures.Depending on disease progression and the surgeon’s preference, the most popular procedures are fasciotomies and fasciectomies. Surgical options for contractures—in increasing order of invasiveness and amounts of fascia removed—are fasciotomy (needle, open), fasciectomy (partial, radical), and dermofasciectomy.

Needle fasciotomy is an outpatient procedure performed under local block. The surgeon uses a needle bevel to transect the diseased cord at multiple puncture sites.

Open fasciotomy is also an outpatient procedure involving an incision that allows direct visualization of the cord and internal structures before dividing the fascia. Percutaneous and open fasciotomies are more successful for MCP joint contractures and less successful for PIP joint contractures.

With partial fasciectomy, only the grossly affected fascia is removed.

With radical fasciectomy, the entire palmar fascia is removed, regardless of which areas are grossly diseased.

Dermofasciectomy removes diseased fascia and the overlying skin, with a skin graft applied to heal the wound.

Another option: Collagenase injection. In February 2010, the US Food and Drug Administration approved collagenase clostridium histolyticum (Xiaflex) as the first drug specifically indicated for the treatment of Dupuytren’s contracture. Collagenase is injected directly into the fascial cord, cleaving its collagen component and progressively softening and breaking down the cord. If not properly injected, collagenase may injure neurovascular structures and may rupture tendons.

So how do the treatment options compare?

We found no randomized prospective trials comparing treatment options for DD, but there are a number of trials that shed light on a variety of the available options.

Treatment success. In general, partial fasciectomies have shown the greatest success in reducing contractures and maintaining the lowest recurrence rates. Correction of contracture to ≤5 degrees was seen in 94% of MCP joint contractures treated with partial fasciectomy, in 77% of MCP joints treated with collagenase, and in 55% of MCP joints treated with percutaneous needle fasciotomies.^22,23 PIP joint contracture correction was not as successful: Correction of contracture to ≤5 degrees was seen in 47% of those treated with partial fasciectomy, 40% treated with collagenase, and 26% treated with needle fasciotomy.^22,23

Recurrence rates. When recurrence was defined as loss of passive extension >30 degrees, the recurrence rate for MCP joint contractures with partial fasciectomy was 21%, compared with 85% for needle fasciotomy.²² In a similar review, recurrence rates for partial fasciectomy ranged from 12% to 39% compared with 50% to 58% for needle fasciotomy.²⁴ With collagenase injection, 5-year data have shown an overall recurrence rate of 32%, with a recurrence of 26% at the MCP joint and 46% at the PIP joint.²⁵ In this trial, recurrence was defined as more than 30% worsening of flexion.²⁵

Complications. Although fasciectomies have shown the best efficacy and lowest recurrence rates, complications such as infection, neurapraxia, and digital nerve injury are more likely with these procedures.^26,27

Early recognition and referral to a hand specialist for the treatment of DD may allow the use of less invasive techniques and improved functional results.

CASE › Absent a history of trauma and features typical of other hand/digit disorders, we diagnosed Dupuytren’s disease in this patient. Potential treatments included partial fasciectomy and collagenase injection. After discussing the risks and benefits of each of these procedures, the patient elected to undergo a partial fasciectomy. The surgery was uncomplicated and the abnormality was corrected to within 5 degrees of full extension. At the patient’s one-year follow-up visit, there was no evidence of recurrence.