Contact Dermatitis

Review the PDF of the fact sheet on dermatoses of pregnancy

After, test your knowledge by answering the 5 practice questions.

Practice Questions

1. Which dermatosis of pregnancy occurs during the third trimester and is associated with multiple gestation pregnancies?

a. atopic eruption of pregnancy

b. gestational pemphigoid

c. intrahepatic cholestasis of pregnancy

d. prurigo of pregnancy

e. pruritic urticarial papules and plaques of pregnancy

2. Which dermatosis of pregnancy frequently flares after delivery?

a. atopic eruption of pregnancy

b. gestational pemphigoid

c. polymorphic eruption of pregnancy

d. prurigo gravidarum

e. prurigo of pregnancy

3. Which dermatosis of pregnancy has lesions that have a predilection for the abdominal striae?

a. cholestasis of pregnancy

b. gestational pemphigoid

c. prurigo gestationis

d. prurigo of pregnancy

e. pruritic urticarial papules and plaques of pregnancy

4. Which dermatosis of pregnancy has a risk for the development of hydatidiform moles and choriocarcinomas?

a. atopic eruption of pregnancy

b. cholestasis of pregnancy

c. gestational pemphigoid

d. pruritic urticarial papules and plaques of pregnancy

e. toxic erythema of pregnancy

5. Intrahepatic cholestasis of pregnancy has been associated with:

a. fetal mortality as high as 13%

b. jaundice in 20% of cases

c. onset in the third trimester of pregnancy

d. recurrence in subsequent pregnancies

e. all of the above
 

The answers appear on the next page.

1. Which dermatosis of pregnancy occurs during the third trimester and is associated with multiple gestation pregnancies?

a. atopic eruption of pregnancy

b. gestational pemphigoid

c. intrahepatic cholestasis of pregnancy

d. prurigo of pregnancy

e. pruritic urticarial papules and plaques of pregnancy

2. Which dermatosis of pregnancy frequently flares after delivery?

a. atopic eruption of pregnancy

b. gestational pemphigoid

c. polymorphic eruption of pregnancy

d. prurigo gravidarum

e. prurigo of pregnancy

3. Which dermatosis of pregnancy has lesions that have a predilection for the abdominal striae?

a. cholestasis of pregnancy

b. gestational pemphigoid

c. prurigo gestationis

d. prurigo of pregnancy

e. pruritic urticarial papules and plaques of pregnancy

4. Which dermatosis of pregnancy has a risk for the development of hydatidiform moles and choriocarcinomas?

a. atopic eruption of pregnancy

b. cholestasis of pregnancy

c. gestational pemphigoid

d. pruritic urticarial papules and plaques of pregnancy

e. toxic erythema of pregnancy

5. Intrahepatic cholestasis of pregnancy has been associated with:

a. fetal mortality as high as 13%

b. jaundice in 20% of cases

c. onset in the third trimester of pregnancy

d. recurrence in subsequent pregnancies

e. all of the above

Review the PDF of the fact sheet on dermatoses of pregnancy

After, test your knowledge by answering the 5 practice questions.

Practice Questions

1. Which dermatosis of pregnancy occurs during the third trimester and is associated with multiple gestation pregnancies?

a. atopic eruption of pregnancy

b. gestational pemphigoid

c. intrahepatic cholestasis of pregnancy

d. prurigo of pregnancy

e. pruritic urticarial papules and plaques of pregnancy

2. Which dermatosis of pregnancy frequently flares after delivery?

a. atopic eruption of pregnancy

b. gestational pemphigoid

c. polymorphic eruption of pregnancy

d. prurigo gravidarum

e. prurigo of pregnancy

3. Which dermatosis of pregnancy has lesions that have a predilection for the abdominal striae?

a. cholestasis of pregnancy

b. gestational pemphigoid

c. prurigo gestationis

d. prurigo of pregnancy

e. pruritic urticarial papules and plaques of pregnancy

4. Which dermatosis of pregnancy has a risk for the development of hydatidiform moles and choriocarcinomas?

a. atopic eruption of pregnancy

b. cholestasis of pregnancy

c. gestational pemphigoid

d. pruritic urticarial papules and plaques of pregnancy

e. toxic erythema of pregnancy

5. Intrahepatic cholestasis of pregnancy has been associated with:

a. fetal mortality as high as 13%

b. jaundice in 20% of cases

c. onset in the third trimester of pregnancy

d. recurrence in subsequent pregnancies

e. all of the above
 

The answers appear on the next page.

1. Which dermatosis of pregnancy occurs during the third trimester and is associated with multiple gestation pregnancies?

a. atopic eruption of pregnancy

b. gestational pemphigoid

c. intrahepatic cholestasis of pregnancy

d. prurigo of pregnancy

e. pruritic urticarial papules and plaques of pregnancy

2. Which dermatosis of pregnancy frequently flares after delivery?

a. atopic eruption of pregnancy

b. gestational pemphigoid

c. polymorphic eruption of pregnancy

d. prurigo gravidarum

e. prurigo of pregnancy

3. Which dermatosis of pregnancy has lesions that have a predilection for the abdominal striae?

a. cholestasis of pregnancy

b. gestational pemphigoid

c. prurigo gestationis

d. prurigo of pregnancy

e. pruritic urticarial papules and plaques of pregnancy

4. Which dermatosis of pregnancy has a risk for the development of hydatidiform moles and choriocarcinomas?

a. atopic eruption of pregnancy

b. cholestasis of pregnancy

c. gestational pemphigoid

d. pruritic urticarial papules and plaques of pregnancy

e. toxic erythema of pregnancy

5. Intrahepatic cholestasis of pregnancy has been associated with:

a. fetal mortality as high as 13%

b. jaundice in 20% of cases

c. onset in the third trimester of pregnancy

d. recurrence in subsequent pregnancies

e. all of the above

Review the PDF of the fact sheet on dermatoses of pregnancy

After, test your knowledge by answering the 5 practice questions.

Practice Questions

1. Which dermatosis of pregnancy occurs during the third trimester and is associated with multiple gestation pregnancies?

a. atopic eruption of pregnancy

b. gestational pemphigoid

c. intrahepatic cholestasis of pregnancy

d. prurigo of pregnancy

e. pruritic urticarial papules and plaques of pregnancy

2. Which dermatosis of pregnancy frequently flares after delivery?

a. atopic eruption of pregnancy

b. gestational pemphigoid

c. polymorphic eruption of pregnancy

d. prurigo gravidarum

e. prurigo of pregnancy

3. Which dermatosis of pregnancy has lesions that have a predilection for the abdominal striae?

a. cholestasis of pregnancy

b. gestational pemphigoid

c. prurigo gestationis

d. prurigo of pregnancy

e. pruritic urticarial papules and plaques of pregnancy

4. Which dermatosis of pregnancy has a risk for the development of hydatidiform moles and choriocarcinomas?

a. atopic eruption of pregnancy

b. cholestasis of pregnancy

c. gestational pemphigoid

d. pruritic urticarial papules and plaques of pregnancy

e. toxic erythema of pregnancy

5. Intrahepatic cholestasis of pregnancy has been associated with:

a. fetal mortality as high as 13%

b. jaundice in 20% of cases

c. onset in the third trimester of pregnancy

d. recurrence in subsequent pregnancies

e. all of the above
 

The answers appear on the next page.

1. Which dermatosis of pregnancy occurs during the third trimester and is associated with multiple gestation pregnancies?

a. atopic eruption of pregnancy

b. gestational pemphigoid

c. intrahepatic cholestasis of pregnancy

d. prurigo of pregnancy

e. pruritic urticarial papules and plaques of pregnancy

2. Which dermatosis of pregnancy frequently flares after delivery?

a. atopic eruption of pregnancy

b. gestational pemphigoid

c. polymorphic eruption of pregnancy

d. prurigo gravidarum

e. prurigo of pregnancy

3. Which dermatosis of pregnancy has lesions that have a predilection for the abdominal striae?

a. cholestasis of pregnancy

b. gestational pemphigoid

c. prurigo gestationis

d. prurigo of pregnancy

e. pruritic urticarial papules and plaques of pregnancy

4. Which dermatosis of pregnancy has a risk for the development of hydatidiform moles and choriocarcinomas?

a. atopic eruption of pregnancy

b. cholestasis of pregnancy

c. gestational pemphigoid

d. pruritic urticarial papules and plaques of pregnancy

e. toxic erythema of pregnancy

5. Intrahepatic cholestasis of pregnancy has been associated with:

a. fetal mortality as high as 13%

b. jaundice in 20% of cases

c. onset in the third trimester of pregnancy

d. recurrence in subsequent pregnancies

e. all of the above

To the Editor:

A 52-year-old man presented to the emergency department with skin pain. Although he felt well overall, he reported that he had developed skin sores 3 weeks prior to presentation that were progressively causing skin pain and sleep loss. He acknowledged smoking cigarettes and snorting cocaine but denied intravenous use of cocaine or using any other drugs. His usual medications were lisinopril and tramadol, and he had no known drug allergies. His history was remarkable for methicillin-resistant Staphylococcus aureus (MRSA) septic arthritis of the shoulder and MRSA prepatellar bursitis within the last 2 years. During examination in the emergency department he was alert, afebrile, nontoxic, generally healthy, and in no acute distress. Extensive necrotic skin lesions were present on the trunk, extremities, and both ears. The lesions were large necrotic patches with irregular, sharply angulated borders with thin or ulcerated epidermis surrounded by a bright halo of erythema (Figure 1). Ulcers were noted on the tongue (Figure 2).

Figure 1. Extensive skin necrosis on the leg from levamisole-contaminated cocaine (A). Necrotic skin lesions also were present on the trunk, arm (B), and ear (C).

Figure 2. Ulcers were noted on the tongue.

The clinical diagnosis was probable thrombosis of skin vessels with skin necrosis due to cocaine that was likely contaminated with levamisole. Pertinent laboratory results included the following: mild anemia and mild leukopenia; values within reference range for liver function, serum protein electrophoresis, hepatitis profile, human immunodeficiency virus 1 and 2, rapid plasma reagin, and antinuclear antibody; normal thrombotic studies for antithrombin III, protein C, protein S, factor V Leiden, prothrombin mutation G20210A, anticardiolipin IgG, IgM, and IgA; erythrocyte sedimentation rate of 
26 mm/h (reference range, 0–15 mm/h); perinuclear antineutrophil cytoplasmic antibody greater than 1:320 (reference range, <1:20) with normal proteinase 3 
and myeloperoxidase antibodies; urine positive for cocaine but blood negative for cocaine; normal chest radiograph; and normal electrocardiogram.

The patient was stable with good family support and was discharged from the emergency department to be followed in our dermatology office. The following day his skin biopsies were interpreted as neutrophilic vasculitis with extensive intravascular early and organizing thrombi involving all small- and medium-sized blood vessels consistent with levamisole-induced necrosis or septic vasculitis (Figure 3). With his history of MRSA septic arthritis and bursitis, he was hospitalized for treatment with intravenous vancomycin pending further studies. Skin biopsy for direct immunofluorescence revealed granular deposits of IgM and linear deposits of C3 at the dermoepidermal junction and in blood vessel walls. Two tissue cultures for bacteria and fungi were negative and 2 blood cultures were negative. An echocardiogram was normal and without evidence of emboli. The patient remained stable and antibiotics were discontinued. He was released from the hospital and his skin lesions healed satisfactorily with showering and mupirocin ointment.

Figure 3. Thrombotic occlusion of blood vessels was seen on histopathology (A and B)(H&E, original magnifications ×100 and ×400).

Cocaine is a white powder that is primarily derived from the leaves of the coca plant in South America. It is ingested orally; injected intravenously; snorted intranasally; chewed; eaten; used as a suppository; or dissolved in water and baking soda then heated to crystallization for smoking, which is the most addictive method and known as freebasing. When smoked, crack cocaine produces a crackling sound. Cocaine stimulates the central nervous system similar to amphetamine but may harm any body organ through vasoconstriction/vasospasm and cause skin necrosis without any additive. Perhaps less known is its ability to produce smooth muscle hyperplasia of small vessels and premature atherosclerosis.¹

Levamisole has been used to treat worms, cancer, and stimulation of the immune system but currently is used only by veterinarians because of agranulocytosis and vasculitis in humans. As of July 2009, the Drug Enforcement Agency reported that 69% of seized cocaine lots coming into the United States contained levamisole.² By January 2010, 73.2% of seized cocaine exhibits contained levamisole according to the California Poison Control System, with reports of contamination rates from across the country ranging from 40% to 90%.³ Levamisole is an inexpensive additive to cocaine and may increase the release of brain dopamine.⁴ It is difficult to detect levamisole in urine due to its short half-life of 
5.6 hours and only 2% to 5% of the parent compound being found in the urine.⁵

Skin necrosis due to cocaine-contaminated levamisole usually occurs in younger individuals who have characteristic skin lesions and a history of cocaine use. Skin lesions usually are multiple, purpuric or necrotic with irregular angulated edges and a halo of erythema. Ear involvement is common but not invariable.⁶ Descriptive adjectives include branched, netlike, retiform, and stellate, all revealing the compromised underlying dermal and subcutaneous vascular anatomy. Supportive evidence includes a decreased white blood cell count (neutropenia in up to 50%),⁵ positive antineutrophilic cytoplasmic antibodies,^5,7 and/or positive drug screen. Skin biopsy may reveal thrombosis,⁴ fibrin thrombi without vasculitis,⁸ or leukocytoclastic vasculitis,^4,5 or may suggest septic vasculitis.⁹ Direct immunofluorescence may suggest an immune complex-mediated vasculitis.⁵

The differential diagnosis for a patient with 
purpuric/necrotic skin lesions should be broad and include vasculitis (eg, inflammatory, antineutrophil cytoplasmic antibody positive, septic), hypercoagulopathy (eg, antiphospholipid syndrome, antithrombin III, prothrombin mutation G20210A, 
factor V Leiden, protein C, protein S), drugs 
(eg, heparin, warfarin, cocaine with or without levamisole, intravenous drug use, hydroxyurea, ergotamine, propylthiouracil¹⁰), calciphylaxis, 
cold-induced thrombosis, emboli (eg, atheroma, cholesterol, endocarditis, myxoma, aortic angiosarcoma, marantic), febrile ulceronecrotic Mucha-Habermann disease, infection especially if immunosuppressed (eg, disseminated Acanthamoeba/Candida/histoplasmosis/strongyloides/varicella-zoster virus, 
S aureus, streptococcus, ecthyma gangrenosum, gas gangrene, hemorrhagic smallpox, lues maligna with human immunodeficiency virus, Meleney ulcer, Rocky Mountain spotted fever, Vibrio vulnificus), idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, thrombocythemia, Waldenström hyperglobulinemic purpura, pyoderma gangrenosum, cancer (eg, paraneoplastic arterial thrombi), oxalosis, paraproteinemia (eg, multiple myeloma), and lupus with generalized coagulopathy. Less likely diagnoses might include Degos disease, factitial dermatitis, foreign bodies, multiple spider bites, paroxysmal nocturnal hemoglobinuria, sickle cell anemia, Buruli ulcer, or thromboangiitis obliterans. Branched, angulated, retiform lesions are an important finding, and some of these diagnostic possibilities are not classically retiform. However, clinical findings are not always classical, and astute physicians want to be circumspect. Had more ominous findings been present in our patient (eg, fever, hemodynamic instability, progressive skin lesions, systemic organ involvement), prompt hospitalization and additional considerations would have been necessary, such as septicemia (eg, meningococcemia, bubonic plague [Black Death], necrotizing 
fasciitis, purpura fulminans), catastrophic antiphospholipid syndrome, or disseminated intra-
vascular coagulation.

The prognosis for skin necrosis caused by 
levamisole-contaminated cocaine generally is good without long-term sequelae.⁵ Autoantibody 
serologies normalize within weeks to months after stopping levamisole.^5,8 Our patient recovered with conservative measures.

To the Editor:

A 52-year-old man presented to the emergency department with skin pain. Although he felt well overall, he reported that he had developed skin sores 3 weeks prior to presentation that were progressively causing skin pain and sleep loss. He acknowledged smoking cigarettes and snorting cocaine but denied intravenous use of cocaine or using any other drugs. His usual medications were lisinopril and tramadol, and he had no known drug allergies. His history was remarkable for methicillin-resistant Staphylococcus aureus (MRSA) septic arthritis of the shoulder and MRSA prepatellar bursitis within the last 2 years. During examination in the emergency department he was alert, afebrile, nontoxic, generally healthy, and in no acute distress. Extensive necrotic skin lesions were present on the trunk, extremities, and both ears. The lesions were large necrotic patches with irregular, sharply angulated borders with thin or ulcerated epidermis surrounded by a bright halo of erythema (Figure 1). Ulcers were noted on the tongue (Figure 2).

Figure 1. Extensive skin necrosis on the leg from levamisole-contaminated cocaine (A). Necrotic skin lesions also were present on the trunk, arm (B), and ear (C).

Figure 2. Ulcers were noted on the tongue.

The clinical diagnosis was probable thrombosis of skin vessels with skin necrosis due to cocaine that was likely contaminated with levamisole. Pertinent laboratory results included the following: mild anemia and mild leukopenia; values within reference range for liver function, serum protein electrophoresis, hepatitis profile, human immunodeficiency virus 1 and 2, rapid plasma reagin, and antinuclear antibody; normal thrombotic studies for antithrombin III, protein C, protein S, factor V Leiden, prothrombin mutation G20210A, anticardiolipin IgG, IgM, and IgA; erythrocyte sedimentation rate of 
26 mm/h (reference range, 0–15 mm/h); perinuclear antineutrophil cytoplasmic antibody greater than 1:320 (reference range, <1:20) with normal proteinase 3 
and myeloperoxidase antibodies; urine positive for cocaine but blood negative for cocaine; normal chest radiograph; and normal electrocardiogram.

The patient was stable with good family support and was discharged from the emergency department to be followed in our dermatology office. The following day his skin biopsies were interpreted as neutrophilic vasculitis with extensive intravascular early and organizing thrombi involving all small- and medium-sized blood vessels consistent with levamisole-induced necrosis or septic vasculitis (Figure 3). With his history of MRSA septic arthritis and bursitis, he was hospitalized for treatment with intravenous vancomycin pending further studies. Skin biopsy for direct immunofluorescence revealed granular deposits of IgM and linear deposits of C3 at the dermoepidermal junction and in blood vessel walls. Two tissue cultures for bacteria and fungi were negative and 2 blood cultures were negative. An echocardiogram was normal and without evidence of emboli. The patient remained stable and antibiotics were discontinued. He was released from the hospital and his skin lesions healed satisfactorily with showering and mupirocin ointment.

Figure 3. Thrombotic occlusion of blood vessels was seen on histopathology (A and B)(H&E, original magnifications ×100 and ×400).

Cocaine is a white powder that is primarily derived from the leaves of the coca plant in South America. It is ingested orally; injected intravenously; snorted intranasally; chewed; eaten; used as a suppository; or dissolved in water and baking soda then heated to crystallization for smoking, which is the most addictive method and known as freebasing. When smoked, crack cocaine produces a crackling sound. Cocaine stimulates the central nervous system similar to amphetamine but may harm any body organ through vasoconstriction/vasospasm and cause skin necrosis without any additive. Perhaps less known is its ability to produce smooth muscle hyperplasia of small vessels and premature atherosclerosis.¹

Levamisole has been used to treat worms, cancer, and stimulation of the immune system but currently is used only by veterinarians because of agranulocytosis and vasculitis in humans. As of July 2009, the Drug Enforcement Agency reported that 69% of seized cocaine lots coming into the United States contained levamisole.² By January 2010, 73.2% of seized cocaine exhibits contained levamisole according to the California Poison Control System, with reports of contamination rates from across the country ranging from 40% to 90%.³ Levamisole is an inexpensive additive to cocaine and may increase the release of brain dopamine.⁴ It is difficult to detect levamisole in urine due to its short half-life of 
5.6 hours and only 2% to 5% of the parent compound being found in the urine.⁵

Skin necrosis due to cocaine-contaminated levamisole usually occurs in younger individuals who have characteristic skin lesions and a history of cocaine use. Skin lesions usually are multiple, purpuric or necrotic with irregular angulated edges and a halo of erythema. Ear involvement is common but not invariable.⁶ Descriptive adjectives include branched, netlike, retiform, and stellate, all revealing the compromised underlying dermal and subcutaneous vascular anatomy. Supportive evidence includes a decreased white blood cell count (neutropenia in up to 50%),⁵ positive antineutrophilic cytoplasmic antibodies,^5,7 and/or positive drug screen. Skin biopsy may reveal thrombosis,⁴ fibrin thrombi without vasculitis,⁸ or leukocytoclastic vasculitis,^4,5 or may suggest septic vasculitis.⁹ Direct immunofluorescence may suggest an immune complex-mediated vasculitis.⁵

The differential diagnosis for a patient with 
purpuric/necrotic skin lesions should be broad and include vasculitis (eg, inflammatory, antineutrophil cytoplasmic antibody positive, septic), hypercoagulopathy (eg, antiphospholipid syndrome, antithrombin III, prothrombin mutation G20210A, 
factor V Leiden, protein C, protein S), drugs 
(eg, heparin, warfarin, cocaine with or without levamisole, intravenous drug use, hydroxyurea, ergotamine, propylthiouracil¹⁰), calciphylaxis, 
cold-induced thrombosis, emboli (eg, atheroma, cholesterol, endocarditis, myxoma, aortic angiosarcoma, marantic), febrile ulceronecrotic Mucha-Habermann disease, infection especially if immunosuppressed (eg, disseminated Acanthamoeba/Candida/histoplasmosis/strongyloides/varicella-zoster virus, 
S aureus, streptococcus, ecthyma gangrenosum, gas gangrene, hemorrhagic smallpox, lues maligna with human immunodeficiency virus, Meleney ulcer, Rocky Mountain spotted fever, Vibrio vulnificus), idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, thrombocythemia, Waldenström hyperglobulinemic purpura, pyoderma gangrenosum, cancer (eg, paraneoplastic arterial thrombi), oxalosis, paraproteinemia (eg, multiple myeloma), and lupus with generalized coagulopathy. Less likely diagnoses might include Degos disease, factitial dermatitis, foreign bodies, multiple spider bites, paroxysmal nocturnal hemoglobinuria, sickle cell anemia, Buruli ulcer, or thromboangiitis obliterans. Branched, angulated, retiform lesions are an important finding, and some of these diagnostic possibilities are not classically retiform. However, clinical findings are not always classical, and astute physicians want to be circumspect. Had more ominous findings been present in our patient (eg, fever, hemodynamic instability, progressive skin lesions, systemic organ involvement), prompt hospitalization and additional considerations would have been necessary, such as septicemia (eg, meningococcemia, bubonic plague [Black Death], necrotizing 
fasciitis, purpura fulminans), catastrophic antiphospholipid syndrome, or disseminated intra-
vascular coagulation.

The prognosis for skin necrosis caused by 
levamisole-contaminated cocaine generally is good without long-term sequelae.⁵ Autoantibody 
serologies normalize within weeks to months after stopping levamisole.^5,8 Our patient recovered with conservative measures.

To the Editor:

A 52-year-old man presented to the emergency department with skin pain. Although he felt well overall, he reported that he had developed skin sores 3 weeks prior to presentation that were progressively causing skin pain and sleep loss. He acknowledged smoking cigarettes and snorting cocaine but denied intravenous use of cocaine or using any other drugs. His usual medications were lisinopril and tramadol, and he had no known drug allergies. His history was remarkable for methicillin-resistant Staphylococcus aureus (MRSA) septic arthritis of the shoulder and MRSA prepatellar bursitis within the last 2 years. During examination in the emergency department he was alert, afebrile, nontoxic, generally healthy, and in no acute distress. Extensive necrotic skin lesions were present on the trunk, extremities, and both ears. The lesions were large necrotic patches with irregular, sharply angulated borders with thin or ulcerated epidermis surrounded by a bright halo of erythema (Figure 1). Ulcers were noted on the tongue (Figure 2).

Figure 1. Extensive skin necrosis on the leg from levamisole-contaminated cocaine (A). Necrotic skin lesions also were present on the trunk, arm (B), and ear (C).

Figure 2. Ulcers were noted on the tongue.

The clinical diagnosis was probable thrombosis of skin vessels with skin necrosis due to cocaine that was likely contaminated with levamisole. Pertinent laboratory results included the following: mild anemia and mild leukopenia; values within reference range for liver function, serum protein electrophoresis, hepatitis profile, human immunodeficiency virus 1 and 2, rapid plasma reagin, and antinuclear antibody; normal thrombotic studies for antithrombin III, protein C, protein S, factor V Leiden, prothrombin mutation G20210A, anticardiolipin IgG, IgM, and IgA; erythrocyte sedimentation rate of 
26 mm/h (reference range, 0–15 mm/h); perinuclear antineutrophil cytoplasmic antibody greater than 1:320 (reference range, <1:20) with normal proteinase 3 
and myeloperoxidase antibodies; urine positive for cocaine but blood negative for cocaine; normal chest radiograph; and normal electrocardiogram.

The patient was stable with good family support and was discharged from the emergency department to be followed in our dermatology office. The following day his skin biopsies were interpreted as neutrophilic vasculitis with extensive intravascular early and organizing thrombi involving all small- and medium-sized blood vessels consistent with levamisole-induced necrosis or septic vasculitis (Figure 3). With his history of MRSA septic arthritis and bursitis, he was hospitalized for treatment with intravenous vancomycin pending further studies. Skin biopsy for direct immunofluorescence revealed granular deposits of IgM and linear deposits of C3 at the dermoepidermal junction and in blood vessel walls. Two tissue cultures for bacteria and fungi were negative and 2 blood cultures were negative. An echocardiogram was normal and without evidence of emboli. The patient remained stable and antibiotics were discontinued. He was released from the hospital and his skin lesions healed satisfactorily with showering and mupirocin ointment.

Figure 3. Thrombotic occlusion of blood vessels was seen on histopathology (A and B)(H&E, original magnifications ×100 and ×400).

Cocaine is a white powder that is primarily derived from the leaves of the coca plant in South America. It is ingested orally; injected intravenously; snorted intranasally; chewed; eaten; used as a suppository; or dissolved in water and baking soda then heated to crystallization for smoking, which is the most addictive method and known as freebasing. When smoked, crack cocaine produces a crackling sound. Cocaine stimulates the central nervous system similar to amphetamine but may harm any body organ through vasoconstriction/vasospasm and cause skin necrosis without any additive. Perhaps less known is its ability to produce smooth muscle hyperplasia of small vessels and premature atherosclerosis.¹

Levamisole has been used to treat worms, cancer, and stimulation of the immune system but currently is used only by veterinarians because of agranulocytosis and vasculitis in humans. As of July 2009, the Drug Enforcement Agency reported that 69% of seized cocaine lots coming into the United States contained levamisole.² By January 2010, 73.2% of seized cocaine exhibits contained levamisole according to the California Poison Control System, with reports of contamination rates from across the country ranging from 40% to 90%.³ Levamisole is an inexpensive additive to cocaine and may increase the release of brain dopamine.⁴ It is difficult to detect levamisole in urine due to its short half-life of 
5.6 hours and only 2% to 5% of the parent compound being found in the urine.⁵

Skin necrosis due to cocaine-contaminated levamisole usually occurs in younger individuals who have characteristic skin lesions and a history of cocaine use. Skin lesions usually are multiple, purpuric or necrotic with irregular angulated edges and a halo of erythema. Ear involvement is common but not invariable.⁶ Descriptive adjectives include branched, netlike, retiform, and stellate, all revealing the compromised underlying dermal and subcutaneous vascular anatomy. Supportive evidence includes a decreased white blood cell count (neutropenia in up to 50%),⁵ positive antineutrophilic cytoplasmic antibodies,^5,7 and/or positive drug screen. Skin biopsy may reveal thrombosis,⁴ fibrin thrombi without vasculitis,⁸ or leukocytoclastic vasculitis,^4,5 or may suggest septic vasculitis.⁹ Direct immunofluorescence may suggest an immune complex-mediated vasculitis.⁵

The differential diagnosis for a patient with 
purpuric/necrotic skin lesions should be broad and include vasculitis (eg, inflammatory, antineutrophil cytoplasmic antibody positive, septic), hypercoagulopathy (eg, antiphospholipid syndrome, antithrombin III, prothrombin mutation G20210A, 
factor V Leiden, protein C, protein S), drugs 
(eg, heparin, warfarin, cocaine with or without levamisole, intravenous drug use, hydroxyurea, ergotamine, propylthiouracil¹⁰), calciphylaxis, 
cold-induced thrombosis, emboli (eg, atheroma, cholesterol, endocarditis, myxoma, aortic angiosarcoma, marantic), febrile ulceronecrotic Mucha-Habermann disease, infection especially if immunosuppressed (eg, disseminated Acanthamoeba/Candida/histoplasmosis/strongyloides/varicella-zoster virus, 
S aureus, streptococcus, ecthyma gangrenosum, gas gangrene, hemorrhagic smallpox, lues maligna with human immunodeficiency virus, Meleney ulcer, Rocky Mountain spotted fever, Vibrio vulnificus), idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, thrombocythemia, Waldenström hyperglobulinemic purpura, pyoderma gangrenosum, cancer (eg, paraneoplastic arterial thrombi), oxalosis, paraproteinemia (eg, multiple myeloma), and lupus with generalized coagulopathy. Less likely diagnoses might include Degos disease, factitial dermatitis, foreign bodies, multiple spider bites, paroxysmal nocturnal hemoglobinuria, sickle cell anemia, Buruli ulcer, or thromboangiitis obliterans. Branched, angulated, retiform lesions are an important finding, and some of these diagnostic possibilities are not classically retiform. However, clinical findings are not always classical, and astute physicians want to be circumspect. Had more ominous findings been present in our patient (eg, fever, hemodynamic instability, progressive skin lesions, systemic organ involvement), prompt hospitalization and additional considerations would have been necessary, such as septicemia (eg, meningococcemia, bubonic plague [Black Death], necrotizing 
fasciitis, purpura fulminans), catastrophic antiphospholipid syndrome, or disseminated intra-
vascular coagulation.

The prognosis for skin necrosis caused by 
levamisole-contaminated cocaine generally is good without long-term sequelae.⁵ Autoantibody 
serologies normalize within weeks to months after stopping levamisole.^5,8 Our patient recovered with conservative measures.

The Diagnosis: Allergic Contact Dermatitis to 
Para-phenylenediamine

To darken the color of henna and increase penetrance and staining, para-phenylenediamine (PPD) is added.¹ Allergic contact dermatitis is the most common type of hypersensitivity to PPD.² A retrospective study that examined severe adverse events from applying henna dyes in children found that angioedema of mucosal tissues was the most common severe adverse event; others included renal failure and shock.³

Black henna is associated with multiple cultural practices. For example, Indian weddings contain a henna decoration ceremony for the bride based on the belief that the longer the henna lasts, the longer the marriage lasts. Black henna is favored for this practice, as it lasts longer than red henna.

Henna (Lawsonia inermis) is a plant that contains the molecule lawsone (naphthoquinone). Lawsone has an intense affinity for keratin; as a result, lawsone is frequently added to temporary body tattoos and hair dyes to create a relatively permanent change in skin or hair color.⁴ Henna is mixed with hennotannic acid to release the lawsone from the plant. Lawsone and hennotannic acid rarely cause allergic reactions.^1,5-7 Once applied to skin, henna takes a few hours to dry, and the resulting color is orange to red.⁸ Often, PPD is added to henna paste to create a black color, to speed up the drying process, and to increase its longevity.

Para-phenylenediamine has been repeatedly reported to cause allergic contact dermatitis. We describe a case of allergic contact dermatitis secondary to PPD in black henna. Our patient is a clear example that PPD is the allergen in black henna given that there was no reaction to the natural red henna tattoo that was applied at the same time to the palmar surfaces of the hands (Figure). Aside from the bullous reaction to black henna dye described here, other reported presentations include erythema multiforme–like and exudative erythema reactions.^9,10

Contact dermatitis lesions from black henna dye can be treated with topical corticosteroids. Patients may develop residual postinflammatory hyperpigmentation or hypopigmentation, leukoderma, keloids, or scars.^1,11,12

The Diagnosis: Allergic Contact Dermatitis to 
Para-phenylenediamine

To darken the color of henna and increase penetrance and staining, para-phenylenediamine (PPD) is added.¹ Allergic contact dermatitis is the most common type of hypersensitivity to PPD.² A retrospective study that examined severe adverse events from applying henna dyes in children found that angioedema of mucosal tissues was the most common severe adverse event; others included renal failure and shock.³

Black henna is associated with multiple cultural practices. For example, Indian weddings contain a henna decoration ceremony for the bride based on the belief that the longer the henna lasts, the longer the marriage lasts. Black henna is favored for this practice, as it lasts longer than red henna.

Henna (Lawsonia inermis) is a plant that contains the molecule lawsone (naphthoquinone). Lawsone has an intense affinity for keratin; as a result, lawsone is frequently added to temporary body tattoos and hair dyes to create a relatively permanent change in skin or hair color.⁴ Henna is mixed with hennotannic acid to release the lawsone from the plant. Lawsone and hennotannic acid rarely cause allergic reactions.^1,5-7 Once applied to skin, henna takes a few hours to dry, and the resulting color is orange to red.⁸ Often, PPD is added to henna paste to create a black color, to speed up the drying process, and to increase its longevity.

Para-phenylenediamine has been repeatedly reported to cause allergic contact dermatitis. We describe a case of allergic contact dermatitis secondary to PPD in black henna. Our patient is a clear example that PPD is the allergen in black henna given that there was no reaction to the natural red henna tattoo that was applied at the same time to the palmar surfaces of the hands (Figure). Aside from the bullous reaction to black henna dye described here, other reported presentations include erythema multiforme–like and exudative erythema reactions.^9,10

Contact dermatitis lesions from black henna dye can be treated with topical corticosteroids. Patients may develop residual postinflammatory hyperpigmentation or hypopigmentation, leukoderma, keloids, or scars.^1,11,12

The Diagnosis: Allergic Contact Dermatitis to 
Para-phenylenediamine

To darken the color of henna and increase penetrance and staining, para-phenylenediamine (PPD) is added.¹ Allergic contact dermatitis is the most common type of hypersensitivity to PPD.² A retrospective study that examined severe adverse events from applying henna dyes in children found that angioedema of mucosal tissues was the most common severe adverse event; others included renal failure and shock.³

Black henna is associated with multiple cultural practices. For example, Indian weddings contain a henna decoration ceremony for the bride based on the belief that the longer the henna lasts, the longer the marriage lasts. Black henna is favored for this practice, as it lasts longer than red henna.

Henna (Lawsonia inermis) is a plant that contains the molecule lawsone (naphthoquinone). Lawsone has an intense affinity for keratin; as a result, lawsone is frequently added to temporary body tattoos and hair dyes to create a relatively permanent change in skin or hair color.⁴ Henna is mixed with hennotannic acid to release the lawsone from the plant. Lawsone and hennotannic acid rarely cause allergic reactions.^1,5-7 Once applied to skin, henna takes a few hours to dry, and the resulting color is orange to red.⁸ Often, PPD is added to henna paste to create a black color, to speed up the drying process, and to increase its longevity.

Para-phenylenediamine has been repeatedly reported to cause allergic contact dermatitis. We describe a case of allergic contact dermatitis secondary to PPD in black henna. Our patient is a clear example that PPD is the allergen in black henna given that there was no reaction to the natural red henna tattoo that was applied at the same time to the palmar surfaces of the hands (Figure). Aside from the bullous reaction to black henna dye described here, other reported presentations include erythema multiforme–like and exudative erythema reactions.^9,10

Contact dermatitis lesions from black henna dye can be treated with topical corticosteroids. Patients may develop residual postinflammatory hyperpigmentation or hypopigmentation, leukoderma, keloids, or scars.^1,11,12

Sodium sulfacetamide has various uses in the field of dermatology due to its anti-inflammatory and antibacterial properties. It has been shown to be effective in the management of a variety of inflammatory facial dermatoses, including papulopustular rosacea, acne vulgaris, seborrheic dermatitis, and perioral dermatitis. We review the mechanism of action, pharmacology and formulations, clinical uses, and adverse effects of sodium sulfacetamide as a dermatologic treatment.

Mechanism of Action

Sodium sulfacetamide is a sulfonamide-type antibacterial agent. Its mechanism of action is the inhibition of bacterial dihydropteroate synthetase, which prevents the conversion of p-aminobenzoic acid to folic acid. This process causes a bacteriostatic effect on the growth of several gram-negative and gram-positive organisms, including Propionibacterium acnes.^1,2

The effectiveness of sodium sulfacetamide is increased when used in combination with sulfur, which has keratolytic, antibacterial, antifungal, and antiparasitic effects. The addition of hydrocortisone has been reported to increase the effectiveness of both agents.³

Pharmacology

Sodium sulfacetamide is highly soluble at the physiologic pH of 7.4, which contributes to its high level of penetration and absorption.⁴ An in vitro study showed percutaneous absorption of sodium sulfacetamide to be around 4%.⁵ Sulfonamides are metabolized mainly by the liver and are excreted by the kidneys.

Formulations

The most common concentrations of sodium sulfacetamide and sulfur are 10% and 5%, respectively. A wide variety of sulfacetamide-containing products are available, many of which are marketed to treat specific conditions depending on additional ingredients or the type of delivery system.

Clinical Uses

Topical formulations of sodium sulfacetamide and sulfur have proven to be efficacious in the management of rosacea, with a typical regimen consisting of twice-daily application for 8 weeks.⁶ The sulfur in the formulation has the additional benefit of targeting Demodex mites, which are implicated as a contributing factor in some cases of rosacea.⁷ Sodium sulfacetamide 10%–sulfur 5% lotion was more effective in improving the erythema, papulopustules, and overall severity of rosacea as compared to metronidazole gel 0.75%.⁸ Other studies have reported increased efficacy when sodium sulfacetamide and topical sulfur are used along with metronidazole.^9,10                

Sodium sulfacetamide also has shown efficacy against acne. Its antibacterial and drying properties have been shown to decrease the number of inflammatory lesions and comedones, and in the treatment of acne vulgaris, no sensitivity reactions have been observed.² Also, unlike topical antibiotics, cases of P acnes resistance to topical sulfur products have not been widely reported. Studies have demonstrated that twice-daily use of sodium sulfacetamide 10%–sulfur 5% for 12 weeks decreases inflammatory acne lesions by 80.4% to 83%.^11,12

Seborrheic dermatitis is a common chronic infection of the skin caused by Malassezia species. One study investigated the use of sodium sulfacetamide ointment and soap to treat seborrheic dermatitis and found that the condition was either improved or completely controlled in 93% (71/76) of cases.⁴ Sodium sulfacetamide lotion was an effective treatment of seborrheic dermatitis in 89% (54/61) of patients with scalp involvement and 68% (30/44) of patients with glabrous skin involvement.¹³

Perioral dermatitis is characterized by groups of erythematous papules and pustules localized around the mouth. The use of topical sodium sulfacetamide along with oral tetracyclines has been demonstrated to consistently clear lesions in most patients with perioral dermatitis.¹⁴ Sodium sulfacetamide is unique in that it is not associated with the excessive erythema and irritation often found with retinoic acid and benzoyl peroxide.¹⁵ Unfortunately, however, there have been no well-controlled trials to compare the efficacy of sodium sulfacetamide to other topical therapies for this condition.

Adverse Effects

Adverse effects from sodium sulfacetamide are rare and generally are limited to cutaneous reactions including dryness, erythema, pruritus, and discomfort.¹ Periocular use of sodium sulfacetamide can cause conjunctival irritation. One study reported that 19% (6/31) of patients experienced local reactions but most were considered mild.⁹ Rare but serious reactions including erythema multiforme and Stevens-Johnson syndrome have been reported from ophthalmic use.^16,17

A common limiting factor to sodium sulfacetamide preparations that include elemental sulfur is the offensive smell, which has hindered patient compliance in the past; however, pharmaceutical companies have attempted to create more tolerable products without the odor.¹⁰ One study found that the tolerability of a sodium sulfacetamide 10%–sulfur 5% foam using a rinse-off method of application was excellent, with only 33% (8/24) of participants commenting on the smell.¹⁸ Another limiting factor of sodium sulfacetamide preparations containing sulfur is orange-brown discoloration when combined with benzoyl peroxide, which does not affect the skin but may stain clothing.¹⁹

Sodium sulfacetamide is rendered less effective when combined with silver-containing products.²⁰ No other notable drug interactions are known; however, oral sulfonamides are known to interact with several drugs, including cyclosporine and phenytoin.^21,22

Contraindications

Sodium sulfacetamide is contraindicated in patients with known hypersensitivity to sulfonamides, sulfur, or any other component of the preparation. It is a pregnancy category C drug, and pregnant women should only use sodium sulfacetamide if it is the only modality to treat the condition or the benefits outweigh the risks. Although there are no known reports of problems related to topical sodium sulfacetamide during pregnancy, the use of oral sulfonamides during pregnancy can increase the risk for neonatal jaundice.²³ Likewise, caution should be exercised in prescribing this product to nursing women, as systemic sulfonamide antibacterials are well known to cause kernicterus in nursing neonates.¹

Conclusion

The efficacy and safety of sodium sulfacetamide, used alone or in combination with sulfur, has been demonstrated in the treatment of rosacea, acne, seborrheic dermatitis, and perioral dermatitis. Advances in formulation technology to decrease odor and irritation have allowed for more use of this product. Further studies will help elucidate the role that sodium sulfacetamide should play in the treatment of inflammatory dermatoses in comparison to other available products.

Sodium sulfacetamide has various uses in the field of dermatology due to its anti-inflammatory and antibacterial properties. It has been shown to be effective in the management of a variety of inflammatory facial dermatoses, including papulopustular rosacea, acne vulgaris, seborrheic dermatitis, and perioral dermatitis. We review the mechanism of action, pharmacology and formulations, clinical uses, and adverse effects of sodium sulfacetamide as a dermatologic treatment.

Mechanism of Action

Sodium sulfacetamide is a sulfonamide-type antibacterial agent. Its mechanism of action is the inhibition of bacterial dihydropteroate synthetase, which prevents the conversion of p-aminobenzoic acid to folic acid. This process causes a bacteriostatic effect on the growth of several gram-negative and gram-positive organisms, including Propionibacterium acnes.^1,2

The effectiveness of sodium sulfacetamide is increased when used in combination with sulfur, which has keratolytic, antibacterial, antifungal, and antiparasitic effects. The addition of hydrocortisone has been reported to increase the effectiveness of both agents.³

Pharmacology

Sodium sulfacetamide is highly soluble at the physiologic pH of 7.4, which contributes to its high level of penetration and absorption.⁴ An in vitro study showed percutaneous absorption of sodium sulfacetamide to be around 4%.⁵ Sulfonamides are metabolized mainly by the liver and are excreted by the kidneys.

Formulations

The most common concentrations of sodium sulfacetamide and sulfur are 10% and 5%, respectively. A wide variety of sulfacetamide-containing products are available, many of which are marketed to treat specific conditions depending on additional ingredients or the type of delivery system.

Clinical Uses

Topical formulations of sodium sulfacetamide and sulfur have proven to be efficacious in the management of rosacea, with a typical regimen consisting of twice-daily application for 8 weeks.⁶ The sulfur in the formulation has the additional benefit of targeting Demodex mites, which are implicated as a contributing factor in some cases of rosacea.⁷ Sodium sulfacetamide 10%–sulfur 5% lotion was more effective in improving the erythema, papulopustules, and overall severity of rosacea as compared to metronidazole gel 0.75%.⁸ Other studies have reported increased efficacy when sodium sulfacetamide and topical sulfur are used along with metronidazole.^9,10                

Sodium sulfacetamide also has shown efficacy against acne. Its antibacterial and drying properties have been shown to decrease the number of inflammatory lesions and comedones, and in the treatment of acne vulgaris, no sensitivity reactions have been observed.² Also, unlike topical antibiotics, cases of P acnes resistance to topical sulfur products have not been widely reported. Studies have demonstrated that twice-daily use of sodium sulfacetamide 10%–sulfur 5% for 12 weeks decreases inflammatory acne lesions by 80.4% to 83%.^11,12

Seborrheic dermatitis is a common chronic infection of the skin caused by Malassezia species. One study investigated the use of sodium sulfacetamide ointment and soap to treat seborrheic dermatitis and found that the condition was either improved or completely controlled in 93% (71/76) of cases.⁴ Sodium sulfacetamide lotion was an effective treatment of seborrheic dermatitis in 89% (54/61) of patients with scalp involvement and 68% (30/44) of patients with glabrous skin involvement.¹³

Perioral dermatitis is characterized by groups of erythematous papules and pustules localized around the mouth. The use of topical sodium sulfacetamide along with oral tetracyclines has been demonstrated to consistently clear lesions in most patients with perioral dermatitis.¹⁴ Sodium sulfacetamide is unique in that it is not associated with the excessive erythema and irritation often found with retinoic acid and benzoyl peroxide.¹⁵ Unfortunately, however, there have been no well-controlled trials to compare the efficacy of sodium sulfacetamide to other topical therapies for this condition.

Adverse Effects

Adverse effects from sodium sulfacetamide are rare and generally are limited to cutaneous reactions including dryness, erythema, pruritus, and discomfort.¹ Periocular use of sodium sulfacetamide can cause conjunctival irritation. One study reported that 19% (6/31) of patients experienced local reactions but most were considered mild.⁹ Rare but serious reactions including erythema multiforme and Stevens-Johnson syndrome have been reported from ophthalmic use.^16,17

A common limiting factor to sodium sulfacetamide preparations that include elemental sulfur is the offensive smell, which has hindered patient compliance in the past; however, pharmaceutical companies have attempted to create more tolerable products without the odor.¹⁰ One study found that the tolerability of a sodium sulfacetamide 10%–sulfur 5% foam using a rinse-off method of application was excellent, with only 33% (8/24) of participants commenting on the smell.¹⁸ Another limiting factor of sodium sulfacetamide preparations containing sulfur is orange-brown discoloration when combined with benzoyl peroxide, which does not affect the skin but may stain clothing.¹⁹

Sodium sulfacetamide is rendered less effective when combined with silver-containing products.²⁰ No other notable drug interactions are known; however, oral sulfonamides are known to interact with several drugs, including cyclosporine and phenytoin.^21,22

Contraindications

Sodium sulfacetamide is contraindicated in patients with known hypersensitivity to sulfonamides, sulfur, or any other component of the preparation. It is a pregnancy category C drug, and pregnant women should only use sodium sulfacetamide if it is the only modality to treat the condition or the benefits outweigh the risks. Although there are no known reports of problems related to topical sodium sulfacetamide during pregnancy, the use of oral sulfonamides during pregnancy can increase the risk for neonatal jaundice.²³ Likewise, caution should be exercised in prescribing this product to nursing women, as systemic sulfonamide antibacterials are well known to cause kernicterus in nursing neonates.¹

Conclusion

The efficacy and safety of sodium sulfacetamide, used alone or in combination with sulfur, has been demonstrated in the treatment of rosacea, acne, seborrheic dermatitis, and perioral dermatitis. Advances in formulation technology to decrease odor and irritation have allowed for more use of this product. Further studies will help elucidate the role that sodium sulfacetamide should play in the treatment of inflammatory dermatoses in comparison to other available products.

Sodium sulfacetamide has various uses in the field of dermatology due to its anti-inflammatory and antibacterial properties. It has been shown to be effective in the management of a variety of inflammatory facial dermatoses, including papulopustular rosacea, acne vulgaris, seborrheic dermatitis, and perioral dermatitis. We review the mechanism of action, pharmacology and formulations, clinical uses, and adverse effects of sodium sulfacetamide as a dermatologic treatment.

Mechanism of Action

Sodium sulfacetamide is a sulfonamide-type antibacterial agent. Its mechanism of action is the inhibition of bacterial dihydropteroate synthetase, which prevents the conversion of p-aminobenzoic acid to folic acid. This process causes a bacteriostatic effect on the growth of several gram-negative and gram-positive organisms, including Propionibacterium acnes.^1,2

The effectiveness of sodium sulfacetamide is increased when used in combination with sulfur, which has keratolytic, antibacterial, antifungal, and antiparasitic effects. The addition of hydrocortisone has been reported to increase the effectiveness of both agents.³

Pharmacology

Sodium sulfacetamide is highly soluble at the physiologic pH of 7.4, which contributes to its high level of penetration and absorption.⁴ An in vitro study showed percutaneous absorption of sodium sulfacetamide to be around 4%.⁵ Sulfonamides are metabolized mainly by the liver and are excreted by the kidneys.

Formulations

The most common concentrations of sodium sulfacetamide and sulfur are 10% and 5%, respectively. A wide variety of sulfacetamide-containing products are available, many of which are marketed to treat specific conditions depending on additional ingredients or the type of delivery system.

Clinical Uses

Topical formulations of sodium sulfacetamide and sulfur have proven to be efficacious in the management of rosacea, with a typical regimen consisting of twice-daily application for 8 weeks.⁶ The sulfur in the formulation has the additional benefit of targeting Demodex mites, which are implicated as a contributing factor in some cases of rosacea.⁷ Sodium sulfacetamide 10%–sulfur 5% lotion was more effective in improving the erythema, papulopustules, and overall severity of rosacea as compared to metronidazole gel 0.75%.⁸ Other studies have reported increased efficacy when sodium sulfacetamide and topical sulfur are used along with metronidazole.^9,10                

Sodium sulfacetamide also has shown efficacy against acne. Its antibacterial and drying properties have been shown to decrease the number of inflammatory lesions and comedones, and in the treatment of acne vulgaris, no sensitivity reactions have been observed.² Also, unlike topical antibiotics, cases of P acnes resistance to topical sulfur products have not been widely reported. Studies have demonstrated that twice-daily use of sodium sulfacetamide 10%–sulfur 5% for 12 weeks decreases inflammatory acne lesions by 80.4% to 83%.^11,12

Seborrheic dermatitis is a common chronic infection of the skin caused by Malassezia species. One study investigated the use of sodium sulfacetamide ointment and soap to treat seborrheic dermatitis and found that the condition was either improved or completely controlled in 93% (71/76) of cases.⁴ Sodium sulfacetamide lotion was an effective treatment of seborrheic dermatitis in 89% (54/61) of patients with scalp involvement and 68% (30/44) of patients with glabrous skin involvement.¹³

Perioral dermatitis is characterized by groups of erythematous papules and pustules localized around the mouth. The use of topical sodium sulfacetamide along with oral tetracyclines has been demonstrated to consistently clear lesions in most patients with perioral dermatitis.¹⁴ Sodium sulfacetamide is unique in that it is not associated with the excessive erythema and irritation often found with retinoic acid and benzoyl peroxide.¹⁵ Unfortunately, however, there have been no well-controlled trials to compare the efficacy of sodium sulfacetamide to other topical therapies for this condition.

Adverse Effects

Adverse effects from sodium sulfacetamide are rare and generally are limited to cutaneous reactions including dryness, erythema, pruritus, and discomfort.¹ Periocular use of sodium sulfacetamide can cause conjunctival irritation. One study reported that 19% (6/31) of patients experienced local reactions but most were considered mild.⁹ Rare but serious reactions including erythema multiforme and Stevens-Johnson syndrome have been reported from ophthalmic use.^16,17

A common limiting factor to sodium sulfacetamide preparations that include elemental sulfur is the offensive smell, which has hindered patient compliance in the past; however, pharmaceutical companies have attempted to create more tolerable products without the odor.¹⁰ One study found that the tolerability of a sodium sulfacetamide 10%–sulfur 5% foam using a rinse-off method of application was excellent, with only 33% (8/24) of participants commenting on the smell.¹⁸ Another limiting factor of sodium sulfacetamide preparations containing sulfur is orange-brown discoloration when combined with benzoyl peroxide, which does not affect the skin but may stain clothing.¹⁹

Sodium sulfacetamide is rendered less effective when combined with silver-containing products.²⁰ No other notable drug interactions are known; however, oral sulfonamides are known to interact with several drugs, including cyclosporine and phenytoin.^21,22

Contraindications

Sodium sulfacetamide is contraindicated in patients with known hypersensitivity to sulfonamides, sulfur, or any other component of the preparation. It is a pregnancy category C drug, and pregnant women should only use sodium sulfacetamide if it is the only modality to treat the condition or the benefits outweigh the risks. Although there are no known reports of problems related to topical sodium sulfacetamide during pregnancy, the use of oral sulfonamides during pregnancy can increase the risk for neonatal jaundice.²³ Likewise, caution should be exercised in prescribing this product to nursing women, as systemic sulfonamide antibacterials are well known to cause kernicterus in nursing neonates.¹

Conclusion

The efficacy and safety of sodium sulfacetamide, used alone or in combination with sulfur, has been demonstrated in the treatment of rosacea, acne, seborrheic dermatitis, and perioral dermatitis. Advances in formulation technology to decrease odor and irritation have allowed for more use of this product. Further studies will help elucidate the role that sodium sulfacetamide should play in the treatment of inflammatory dermatoses in comparison to other available products.

The active ingredient of any pharmaceutical product is responsible for the agent’s efficacy and safety profile. This ingredient is extensively studied in clinical trials and evaluated by the US Food and Drug Administration before the product is commercially available. In dermatologic products, especially those for treating dermatoses, the vehicle in which the active ingredient is formulated also plays a role in drug delivery and indirectly impacts therapeutic outcomes, unlike excipients in oral medications. Topical vehicles must be stable, provide a suitable environment that will not degrade the active ingredient or affect its efficacy, and be cosmetically acceptable.¹

Topical vehicles are formulated to maintain the stability of the active ingredient and allow it to readily penetrate the skin and reach its target area with minimal absorption into the bloodstream, thus avoiding systemic adverse events. A variety of vehicles can exist for a single active ingredient to accommodate different phases of disease and different anatomical sites where the disease may occur.² For example, alcohol-based vehicles, sprays, and foams are preferred for the scalp where evaporation of the vehicle is beneficial to prevent greasiness of the hair, while ointments may be preferred due to their occlusive nature for areas with xerotic or thick skin from dermatoses.

Cosmetic acceptability of the vehicle may influence patient adherence to therapy. Housman et al³ assessed a variety of products formulated in different vehicles (ie, solutions, foams, emollients, gels, creams, ointments) for the treatment of psoriasis. Patients with psoriasis applied each test product to a quarter-sized area of normal skin on the forearm using a cotton swab and completed a preference questionnaire. By far, respondents significantly preferred solutions and foams over creams, gels, and ointments (P<.01). Side effects were rated to be the most important characteristics of topical therapy, followed by time needed for application, ease of application, and messiness.³ Presumably, if patients are frustrated with the topical product that they are using, adherence to the prescribed dosage and application instructions will diminish over time, leading to suboptimal steady-state levels of the product. If appropriate levels of the drug are not present at the target site, treatment will not be successful.

Steady-state levels of a topical drug at the site of action also are maintained via appropriate application frequency, most commonly once to 4 times daily for dermatologic products. Fluocinonide and halcinonide are class II (potent) corticosteroids indicated for the relief of inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses and usually are administered at least twice daily. In double-blind clinical studies comparing both products in the treatment of psoriasis, halcinonide resulted in more improved outcomes than fluocinonide.^4-6 Sudilovsky and Clewe⁴ studied 140 patients with moderate to severe psoriasis. After 3 weeks of treatment, 44% showed superior results with halcinonide, 27% showed superior results with fluocinonide, 26% showed equal results with both products, and 3% showed no relief.⁴ Similarly, Close⁵ reported that 61% of patients showed superior results with halcinonide, 25% showed superior results with fluocinonide, 10% showed equal results with both products, and 4% showed no relief (N=50). Lynfield and Watsky⁶ reported that 56% of patients with severe psoriasis who were treated with halcinonide for 2 weeks showed improvement to normal or slight inflammation compared to 44% of patients treated with fluocinonide (N=59). All 3 studies used cream formulations of halcinonide and fluocinonide.

Recently, halcinonide cream was shown to have an immediate release into the stratum corneum that peaked within 1 hour of application and remained elevated for 6 hours before beginning to decline.⁷ These results support a biphasic release of halcinonide, which is in agreement with its formulation—that halcinonide exists in both a solution phase for immediate release into the skin and in a suspension phase that allows a sustained release after equilibrium is reached between the solution and suspension phases.⁸ Fluocinonide is not known to be formulated in a similar way. Its vehicle composition and penetration into the skin could explain the superior efficacy of halcinonide versus fluocinonide.

The current pilot study was conducted to compare the release pattern of fluocinonide cream versus halcinonide cream into the stratum corneum using an in vivo, noninvasive method. Results for halcin-onide have been previously published.⁷

Methods

Participants were sequestered in a controlled environment for the entire day to allow the skin to equilibrate prior to product application. The methodology for the application and quantification of halcinonide cream 0.1% into the stratum corneum of 5 participants using a tape-stripping protocol has been described elsewhere.⁷ Concordia Clinical Research institutional review board (Cedar Knolls, New Jersey) approved this study, which was conducted at Dermatology Consulting Services (High Point, North Carolina).

A 0.1-g dose of generic fluocinonide cream 0.05% was applied to four 2.5-cm circular sites on the forearm in 5 participants with normal skin until completely absorbed. Circular tape strips were subsequently placed on the application site at 1, 3, 6, and 9 hours posttreatment and were held for 10 seconds with a controlled pressure plunger to ensure adequate and consistent contact between the tape strip and the skin. The tape strip was removed with forceps, rolled with the skin scale inside, and placed in a glass vial. This procedure was repeated 6 times at 1 of 4 sites with a new tape strip at each time point to obtain samples from deeper skin layers. A total of 24 tape strips were collected from each participant.

All vials were frozen at -20°C and were shipped overnight to Robert Kellar, PhD, at the Center for Bioengineering Innovation at Northern Arizona University (Flagstaff, Arizona) for mass spectroscopy evaluation. Once received at the outside facility, the vials were stored at -20°C until analysis. Each sample was spiked with a known quantity of an appropriate reference standard and extracted with 1 mL acetonitrile at room temperature for 1 minute with agitation. New unused tape strips were spiked with a small amount of fluocinonide reference standard for extraction efficiency.

Extracts were evaporated to dryness under nitrogen gas, resuspended in 200 µL chromatography solvent, and quantified using liquid chromatography–mass spectrometry. To remove the skin scale from the tape strips, 10 mL of a solvent solution of 0.1 mg/mL fludrocortisone acetate in acetonitrile was dispensed into a 4 dram vial containing the tape strip. The vials were ultrasonicated and shaken for 10 to 15 minutes, and the samples were further diluted to 100-fold and were inverted several times to ensure complete dissolution of fluocinonide before liquid chromatography–mass spectrometry.

A standard curve ranging from the lower limit of quantification to the upper limit of quantification for the fluocinonide reference was used to determine the quantity of fluocinonide in each of the tape strips. Once the lower limit of quantification was reached in a given set of tape strip samples (1-, 3-, 6-, and 9-hour samples), the next 2 sequential tape strips in that set were analyzed to confirm fluocinonide was not detectable in deeper layers. Standard quality controls were analyzed to ensure run-to-run and sample-to-sample accuracy.

Each sample was analyzed in duplicate; 10 mg fluocinonide was used as a reference standard. The minimum detectable concentration of fluocinonide was 1 ng/mL.

Results

As expected, tape strip 1 from each participant contained the highest concentration of fluocinonide. This strip corresponded to the most superficial layer of skin. Concentrations decreased in deeper skin layers, as detected in strips 2 to 6.

In general, the average concentration of fluocin-onide in strip 1 for all 5 participants was highest at hour 1, with a subsequent decline at hours 3, 6, and 9; however, participant 1 showed a second peak in fluocinonide concentration at hour 6 (Figure 1). When the fluocinonide concentration in strips 1 to 6 was averaged for each participant at each time point, similar results were obtained: a general decline after hour 1, but a second prominent peak at hour 6 in participant 1 only. In participant 1, the average fluocinonide concentration for strips 1 to 6 was 393 ng/mL at hour 1 and declined to 208 ng/mL at hour 3; it increased to 451 ng/mL at hour 6 before declining again to 202 ng/mL at hour 9.

Figure 1. Fluocinonide concentration in tape strip 1 for all participants (N=5).

Because participant 1 was the only one to exhibit a second peak of fluocinonide concentration, it appears that measurements obtained from this participant may be outliers. When removing partici-pant 1 from the analysis of fluocinonide concentration in strip 1 at each time point, a clear decline is evident from hour 1 to hour 9 (Figure 2A, red line [partici-pants 2–5] vs blue line [participants 1–5]).

When the average concentration of fluocinonide was calculated in strips 1 to 6 from all participants, there was a general steady decline after hour 1 with a slight increase of 25 ng/mL at hour 6 (Figure 2B, blue line). This increase is due to the measurements obtained from participant 1; however, if partici-pant 1 is removed from the analysis, a constant decline is observed from hour 1 to hour 9 (Figure 2B, red line).

Figure 2. Average fluocinonide concentration in tape strip 1 only (A) and strips 1 to 6 (B)(N=5). Error bars indicate standard deviation.

A prior study evaluated the penetration and absorption of halcinonide in the stratum corneum.⁷ In summary, halcinonide concentration peaked at hour 1 following application and remained elevated to hour 6, before beginning a slow decline. The average concentration of halcinonide from all participants in strips 1 to 6 reached 1350 ng/mL at hour 1, remained within 93% to 97% of this level (1253–1303 ng/mL) for the next 5 hours, and declined only 29% from the peak at hour 1 to hour 9 (958 ng/mL)(Figure 3, blue line).⁷ In contrast, the fluocinonide concentration in participants 2 to 5 from the current study reached 190 ng/mL at hour 1 and steadily declined 53% to 89 ng/mL by hour 9 (Figure 3, red line).

Figure 3. Average halcinonide and fluocinonide concentrations in tape strips 1 to 6 (N=5 for both). Adapted from Draelos.7 7

Two participants from the prior halcinonide study also were enrolled in the current fluocinonide study (referred to as participant A and B). In general, halcinonide levels in both participants remained elevated for 6 hours after application and declined 27.5% and 35.5%, respectively, by hour 9 (Figure 4). Participant A experienced a 20.5% dip in halcinonide concentration at hour 3 followed by an increase at hour 6; however, the halcinonide concentration at hour 9 was similar to hour 3.⁷ In contrast, fluocin-onide concentrations for these participants peaked at 1 hour and clearly declined approximately 60% over the next 8 hours.

Figure 4. Fluocinonide and halcin-onide concentrations in tape strips 1 to 6 for 2 participants who received both corticosteroids during different study periods (referred to as participant A and B).

Comment

The release of both fluocinonide and halcinonide into the skin was evaluated using dermal tape stripping on 4 sites on the forearms of healthy individuals. Cream formulations of each corticosteroid were evaluated in 5 participants, with 2 participants receiving both formulations during different study periods. In the prior study with halcinonide, the stratum corneum exhibited the highest concentration of the corticosteroid, with substantial declines beyond strip 6 (ie, strips 7–20).⁷ For this reason, only strips 1 to 6 were evaluated for corticosteroid penetration and absorption.

Results from strip 1 indicated immediate absorption of corticosteroid (fluocinonide and halcinonide) into the skin. Unlike the release of halcinonide, which demonstrated a clear sustained release over 6 hours before decreasing,⁷ fluocinonide concentrations began declining immediately after peaking at hour 1 and continued to decline up to hour 9. Only participant 1 exhibited a second peak of fluocinonide concentration at hour 6; the rest of the participants did not. This second peak is most likely an anomaly due to the small number of participants rather than a true elevation.

Given the rapid decline of fluocinonide concentration over the 9 hours compared with the more gradual decline of halcinonide concentration, there appears to be no evidence of a biphasic sustained release of fluocinonide from its vehicle. This difference in release pattern from each corticosteroid’s respective vehicle may explain in part the different clinical outcomes in comparative studies.^4-6

It is known that vehicle composition affects corticosteroid diffusion from the vehicle to the skin surface and subsequent penetration into the skin.⁹ Either process can determine the overall effectiveness of the product. Ayres and Hooper¹⁰ evaluated the penetration of 4 topical preparations of cortisol. Product 1 delivered 16 times more cortisol to the skin than product 2, 8 times more than product 3, and 3 times more than product 4. Because all the preparations contained cortisol-free alcohol, these differences were attributed to the vehicle in which the cortisol was formulated. Products 1 and 4 both contained 10% urea, but the urea in product 1 was a powder in a cream base and the urea in product 4 was in a stabilizing emulsified base. Product 2 contained a propylene glycol/water base and product 3 was a water-miscible cream.¹⁰

Generic corticosteroid products have been observed in clinical practice and have been shown in vasoconstriction assays to be less and more potent than their brand-name equivalents.^2,11 Vasoconstriction assays are the standard for assessing the potency of topical corticosteroids and predicting their clinical efficacy.² One study reported significant differences in therapeutic effectiveness between generic formulations and their brand-name equivalents.¹² Kenalog cream 0.1% (multiple manufacturers) was significantly more potent than any of the generic triamcinolone creams tested (P<.05); in fact, Kenalog cream 0.025% (multiple manufacturers) was statistically superior to all the generic triamcinolone creams 0.1%. Moreover, Artistocort A ointment 0.1% (Lederele Laboratories) and Valisone cream 0.1% (Schering Corporation) also were more potent than their generics at the same concentration in the same vehicle type.¹² A second study also observed that 2 of 6 generic formulations had significantly less vasoconstriction than their respective brand-name formulations.¹¹ A brand-name betamethasone valerate cream produced significantly greater vasoconstriction than its generic equivalent, and a brand-name betamethasone dipropionate cream produced greater vasoconstriction than one generic and equal vasoconstriction to another generic. Additionally, the vasoconstriction measured with Diprosone was greater than that measured with Diprolene, another brand-name product of betamethasone dipropionate.¹¹ Diprosone and Diprolene differ in their vehicle content. The latter, a class I corticosteroid, contains a modified vehicle high in propylene glycol, whereas the former contains less propylene glycol and thus is classified as a class III corticosteroid. Propylene glycol allows hydrophobic molecules such as corticosteroids to dissolve more fully in the vehicle.¹²

Ostrenga et al¹ studied the solubility of corticosteroids in different vehicles and, as expected, corticosteroids that fully solubilized in the vehicle exhibited better penetration into the skin on assessment with vasoconstriction assays. Corticosteroids in a suspension, on the other hand, showed slower penetration into the skin.^1,13 A balance between the solution and suspension phase would allow a drug to rapidly penetrate the skin upon application, and when this pool of solubilized drug was depleted, additional drug could penetrate into the skin from the suspension phase. Based on the tape strip results from the current study it appears that halcinonide, which is manufactured in a biphasic formulation, follows this pattern of penetration and absorption into the stratum corneum. In contrast, fluocinonide appears to exist in a soluble state without much, if any, amount in a suspension phase because it had no sustained release during the 9 hours after application.

Common belief among dermatologists is that long-term use of corticosteroids leads to tachyphylaxis,¹⁴ which can be attributed to poor patient adherence. If patients skip doses, then the steady state of the product at the target site is not maintained. It is interesting to speculate that using agents with more sustained release beyond the time of application (such as halcinonide) may preserve steady-state levels even when patients are neglectful of the next medication application. Corticosteroids that work in 2 phases such as halcinonide may minimize tachyphylaxis experienced with prolonged use of corticosteroids.

Fluocinonide and halcinonide are both class II high-potency corticosteroids as shown on outcomes from vasoconstrictor assays, which assess the extent to which a corticosteroid causes cutaneous vasoconstriction or blanching in normal healthy individuals.¹⁵ The assay depends on the molecule diffusing from the vehicle, penetrating the skin, and causing a reaction (blanching) that is then evaluated. The assay cannot effectively evaluate the rate of continued diffusion and skin penetration beyond the appearance of blanching. In contrast, the tape-stripping method provides an inside look at the extent of penetration of the corticosteroid beyond the skin surface and the rate of its clearance from different skin layers. In the current study, the levels of fluocinonide declined after peaking at 1 hour after application, but the levels of halcinonide clearly remained elevated after peaking at the same time point. Most likely, vasoconstrictor studies would not be able to differentiate between the concentrations of the 2 products in the stratum corneum beyond the first hour after application.

Tape stripping, or dermatopharmacokinetics, has advantages over vasoconstriction assays in studying corticosteroid penetration and clearance from the stratum corneum. At one point, the US Food and Drug Administration had included tape stripping in its preliminary guidelines for generic topical bioequivalence studies until data from the same formulation generated from 2 different laboratories produced different results.¹⁶ Since that time, much work has been done with tape stripping to ensure its consistency. Weigmann et al¹⁷ demonstrated equivalent results with clobetasol using vasoconstriction and tape stripping, and Wiedersberg et al¹⁸ demonstrated the same with betamethasone. For the current study, the fluocinonide and halcinonide formulations were weighed prior to application so that the same dose was tested in all participants. A plunger was used to produce consistent pressure at all application sites to control for the amount of skin that was stripped off with the tape. Results for both corticosteroids were consistent between the participants. Variability in the data was detected; however, this observation is most likely due to the small number of participants in the studies.

Conclusion

In summary, this pilot study demonstrated that fluocinonide concentration in the stratum corneum peaks within the first hour of application before beginning a steady general decline. There was no evidence of sustained release. In contrast, halcin-onide demonstrated a sustained release for 6 hours after application. Halcinonide is formulated in a cream base in which the corticosteroid is present in a solution and suspension phase that allows for sustained delivery in skin over time. Fluocinonide does not appear to be formulated in the same way, and its concentrations in the stratum corneum begin to decline 1 hour after application.

Acknowledgement

Thank you to Robert Kellar, PhD, at the Center for Bioengineering Innovation at Northern Arizona University, Flagstaff, for conducting the liquid chromatography–mass spectrometry.

The active ingredient of any pharmaceutical product is responsible for the agent’s efficacy and safety profile. This ingredient is extensively studied in clinical trials and evaluated by the US Food and Drug Administration before the product is commercially available. In dermatologic products, especially those for treating dermatoses, the vehicle in which the active ingredient is formulated also plays a role in drug delivery and indirectly impacts therapeutic outcomes, unlike excipients in oral medications. Topical vehicles must be stable, provide a suitable environment that will not degrade the active ingredient or affect its efficacy, and be cosmetically acceptable.¹

Topical vehicles are formulated to maintain the stability of the active ingredient and allow it to readily penetrate the skin and reach its target area with minimal absorption into the bloodstream, thus avoiding systemic adverse events. A variety of vehicles can exist for a single active ingredient to accommodate different phases of disease and different anatomical sites where the disease may occur.² For example, alcohol-based vehicles, sprays, and foams are preferred for the scalp where evaporation of the vehicle is beneficial to prevent greasiness of the hair, while ointments may be preferred due to their occlusive nature for areas with xerotic or thick skin from dermatoses.

Cosmetic acceptability of the vehicle may influence patient adherence to therapy. Housman et al³ assessed a variety of products formulated in different vehicles (ie, solutions, foams, emollients, gels, creams, ointments) for the treatment of psoriasis. Patients with psoriasis applied each test product to a quarter-sized area of normal skin on the forearm using a cotton swab and completed a preference questionnaire. By far, respondents significantly preferred solutions and foams over creams, gels, and ointments (P<.01). Side effects were rated to be the most important characteristics of topical therapy, followed by time needed for application, ease of application, and messiness.³ Presumably, if patients are frustrated with the topical product that they are using, adherence to the prescribed dosage and application instructions will diminish over time, leading to suboptimal steady-state levels of the product. If appropriate levels of the drug are not present at the target site, treatment will not be successful.

Steady-state levels of a topical drug at the site of action also are maintained via appropriate application frequency, most commonly once to 4 times daily for dermatologic products. Fluocinonide and halcinonide are class II (potent) corticosteroids indicated for the relief of inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses and usually are administered at least twice daily. In double-blind clinical studies comparing both products in the treatment of psoriasis, halcinonide resulted in more improved outcomes than fluocinonide.^4-6 Sudilovsky and Clewe⁴ studied 140 patients with moderate to severe psoriasis. After 3 weeks of treatment, 44% showed superior results with halcinonide, 27% showed superior results with fluocinonide, 26% showed equal results with both products, and 3% showed no relief.⁴ Similarly, Close⁵ reported that 61% of patients showed superior results with halcinonide, 25% showed superior results with fluocinonide, 10% showed equal results with both products, and 4% showed no relief (N=50). Lynfield and Watsky⁶ reported that 56% of patients with severe psoriasis who were treated with halcinonide for 2 weeks showed improvement to normal or slight inflammation compared to 44% of patients treated with fluocinonide (N=59). All 3 studies used cream formulations of halcinonide and fluocinonide.

Recently, halcinonide cream was shown to have an immediate release into the stratum corneum that peaked within 1 hour of application and remained elevated for 6 hours before beginning to decline.⁷ These results support a biphasic release of halcinonide, which is in agreement with its formulation—that halcinonide exists in both a solution phase for immediate release into the skin and in a suspension phase that allows a sustained release after equilibrium is reached between the solution and suspension phases.⁸ Fluocinonide is not known to be formulated in a similar way. Its vehicle composition and penetration into the skin could explain the superior efficacy of halcinonide versus fluocinonide.

The current pilot study was conducted to compare the release pattern of fluocinonide cream versus halcinonide cream into the stratum corneum using an in vivo, noninvasive method. Results for halcin-onide have been previously published.⁷

Methods

Participants were sequestered in a controlled environment for the entire day to allow the skin to equilibrate prior to product application. The methodology for the application and quantification of halcinonide cream 0.1% into the stratum corneum of 5 participants using a tape-stripping protocol has been described elsewhere.⁷ Concordia Clinical Research institutional review board (Cedar Knolls, New Jersey) approved this study, which was conducted at Dermatology Consulting Services (High Point, North Carolina).

A 0.1-g dose of generic fluocinonide cream 0.05% was applied to four 2.5-cm circular sites on the forearm in 5 participants with normal skin until completely absorbed. Circular tape strips were subsequently placed on the application site at 1, 3, 6, and 9 hours posttreatment and were held for 10 seconds with a controlled pressure plunger to ensure adequate and consistent contact between the tape strip and the skin. The tape strip was removed with forceps, rolled with the skin scale inside, and placed in a glass vial. This procedure was repeated 6 times at 1 of 4 sites with a new tape strip at each time point to obtain samples from deeper skin layers. A total of 24 tape strips were collected from each participant.

All vials were frozen at -20°C and were shipped overnight to Robert Kellar, PhD, at the Center for Bioengineering Innovation at Northern Arizona University (Flagstaff, Arizona) for mass spectroscopy evaluation. Once received at the outside facility, the vials were stored at -20°C until analysis. Each sample was spiked with a known quantity of an appropriate reference standard and extracted with 1 mL acetonitrile at room temperature for 1 minute with agitation. New unused tape strips were spiked with a small amount of fluocinonide reference standard for extraction efficiency.

Extracts were evaporated to dryness under nitrogen gas, resuspended in 200 µL chromatography solvent, and quantified using liquid chromatography–mass spectrometry. To remove the skin scale from the tape strips, 10 mL of a solvent solution of 0.1 mg/mL fludrocortisone acetate in acetonitrile was dispensed into a 4 dram vial containing the tape strip. The vials were ultrasonicated and shaken for 10 to 15 minutes, and the samples were further diluted to 100-fold and were inverted several times to ensure complete dissolution of fluocinonide before liquid chromatography–mass spectrometry.

A standard curve ranging from the lower limit of quantification to the upper limit of quantification for the fluocinonide reference was used to determine the quantity of fluocinonide in each of the tape strips. Once the lower limit of quantification was reached in a given set of tape strip samples (1-, 3-, 6-, and 9-hour samples), the next 2 sequential tape strips in that set were analyzed to confirm fluocinonide was not detectable in deeper layers. Standard quality controls were analyzed to ensure run-to-run and sample-to-sample accuracy.

Each sample was analyzed in duplicate; 10 mg fluocinonide was used as a reference standard. The minimum detectable concentration of fluocinonide was 1 ng/mL.

Results

As expected, tape strip 1 from each participant contained the highest concentration of fluocinonide. This strip corresponded to the most superficial layer of skin. Concentrations decreased in deeper skin layers, as detected in strips 2 to 6.

In general, the average concentration of fluocin-onide in strip 1 for all 5 participants was highest at hour 1, with a subsequent decline at hours 3, 6, and 9; however, participant 1 showed a second peak in fluocinonide concentration at hour 6 (Figure 1). When the fluocinonide concentration in strips 1 to 6 was averaged for each participant at each time point, similar results were obtained: a general decline after hour 1, but a second prominent peak at hour 6 in participant 1 only. In participant 1, the average fluocinonide concentration for strips 1 to 6 was 393 ng/mL at hour 1 and declined to 208 ng/mL at hour 3; it increased to 451 ng/mL at hour 6 before declining again to 202 ng/mL at hour 9.

Figure 1. Fluocinonide concentration in tape strip 1 for all participants (N=5).

Because participant 1 was the only one to exhibit a second peak of fluocinonide concentration, it appears that measurements obtained from this participant may be outliers. When removing partici-pant 1 from the analysis of fluocinonide concentration in strip 1 at each time point, a clear decline is evident from hour 1 to hour 9 (Figure 2A, red line [partici-pants 2–5] vs blue line [participants 1–5]).

When the average concentration of fluocinonide was calculated in strips 1 to 6 from all participants, there was a general steady decline after hour 1 with a slight increase of 25 ng/mL at hour 6 (Figure 2B, blue line). This increase is due to the measurements obtained from participant 1; however, if partici-pant 1 is removed from the analysis, a constant decline is observed from hour 1 to hour 9 (Figure 2B, red line).

Figure 2. Average fluocinonide concentration in tape strip 1 only (A) and strips 1 to 6 (B)(N=5). Error bars indicate standard deviation.

A prior study evaluated the penetration and absorption of halcinonide in the stratum corneum.⁷ In summary, halcinonide concentration peaked at hour 1 following application and remained elevated to hour 6, before beginning a slow decline. The average concentration of halcinonide from all participants in strips 1 to 6 reached 1350 ng/mL at hour 1, remained within 93% to 97% of this level (1253–1303 ng/mL) for the next 5 hours, and declined only 29% from the peak at hour 1 to hour 9 (958 ng/mL)(Figure 3, blue line).⁷ In contrast, the fluocinonide concentration in participants 2 to 5 from the current study reached 190 ng/mL at hour 1 and steadily declined 53% to 89 ng/mL by hour 9 (Figure 3, red line).

Figure 3. Average halcinonide and fluocinonide concentrations in tape strips 1 to 6 (N=5 for both). Adapted from Draelos.7 7

Two participants from the prior halcinonide study also were enrolled in the current fluocinonide study (referred to as participant A and B). In general, halcinonide levels in both participants remained elevated for 6 hours after application and declined 27.5% and 35.5%, respectively, by hour 9 (Figure 4). Participant A experienced a 20.5% dip in halcinonide concentration at hour 3 followed by an increase at hour 6; however, the halcinonide concentration at hour 9 was similar to hour 3.⁷ In contrast, fluocin-onide concentrations for these participants peaked at 1 hour and clearly declined approximately 60% over the next 8 hours.

Figure 4. Fluocinonide and halcin-onide concentrations in tape strips 1 to 6 for 2 participants who received both corticosteroids during different study periods (referred to as participant A and B).

Comment

The release of both fluocinonide and halcinonide into the skin was evaluated using dermal tape stripping on 4 sites on the forearms of healthy individuals. Cream formulations of each corticosteroid were evaluated in 5 participants, with 2 participants receiving both formulations during different study periods. In the prior study with halcinonide, the stratum corneum exhibited the highest concentration of the corticosteroid, with substantial declines beyond strip 6 (ie, strips 7–20).⁷ For this reason, only strips 1 to 6 were evaluated for corticosteroid penetration and absorption.

Results from strip 1 indicated immediate absorption of corticosteroid (fluocinonide and halcinonide) into the skin. Unlike the release of halcinonide, which demonstrated a clear sustained release over 6 hours before decreasing,⁷ fluocinonide concentrations began declining immediately after peaking at hour 1 and continued to decline up to hour 9. Only participant 1 exhibited a second peak of fluocinonide concentration at hour 6; the rest of the participants did not. This second peak is most likely an anomaly due to the small number of participants rather than a true elevation.

Given the rapid decline of fluocinonide concentration over the 9 hours compared with the more gradual decline of halcinonide concentration, there appears to be no evidence of a biphasic sustained release of fluocinonide from its vehicle. This difference in release pattern from each corticosteroid’s respective vehicle may explain in part the different clinical outcomes in comparative studies.^4-6

It is known that vehicle composition affects corticosteroid diffusion from the vehicle to the skin surface and subsequent penetration into the skin.⁹ Either process can determine the overall effectiveness of the product. Ayres and Hooper¹⁰ evaluated the penetration of 4 topical preparations of cortisol. Product 1 delivered 16 times more cortisol to the skin than product 2, 8 times more than product 3, and 3 times more than product 4. Because all the preparations contained cortisol-free alcohol, these differences were attributed to the vehicle in which the cortisol was formulated. Products 1 and 4 both contained 10% urea, but the urea in product 1 was a powder in a cream base and the urea in product 4 was in a stabilizing emulsified base. Product 2 contained a propylene glycol/water base and product 3 was a water-miscible cream.¹⁰

Generic corticosteroid products have been observed in clinical practice and have been shown in vasoconstriction assays to be less and more potent than their brand-name equivalents.^2,11 Vasoconstriction assays are the standard for assessing the potency of topical corticosteroids and predicting their clinical efficacy.² One study reported significant differences in therapeutic effectiveness between generic formulations and their brand-name equivalents.¹² Kenalog cream 0.1% (multiple manufacturers) was significantly more potent than any of the generic triamcinolone creams tested (P<.05); in fact, Kenalog cream 0.025% (multiple manufacturers) was statistically superior to all the generic triamcinolone creams 0.1%. Moreover, Artistocort A ointment 0.1% (Lederele Laboratories) and Valisone cream 0.1% (Schering Corporation) also were more potent than their generics at the same concentration in the same vehicle type.¹² A second study also observed that 2 of 6 generic formulations had significantly less vasoconstriction than their respective brand-name formulations.¹¹ A brand-name betamethasone valerate cream produced significantly greater vasoconstriction than its generic equivalent, and a brand-name betamethasone dipropionate cream produced greater vasoconstriction than one generic and equal vasoconstriction to another generic. Additionally, the vasoconstriction measured with Diprosone was greater than that measured with Diprolene, another brand-name product of betamethasone dipropionate.¹¹ Diprosone and Diprolene differ in their vehicle content. The latter, a class I corticosteroid, contains a modified vehicle high in propylene glycol, whereas the former contains less propylene glycol and thus is classified as a class III corticosteroid. Propylene glycol allows hydrophobic molecules such as corticosteroids to dissolve more fully in the vehicle.¹²

Ostrenga et al¹ studied the solubility of corticosteroids in different vehicles and, as expected, corticosteroids that fully solubilized in the vehicle exhibited better penetration into the skin on assessment with vasoconstriction assays. Corticosteroids in a suspension, on the other hand, showed slower penetration into the skin.^1,13 A balance between the solution and suspension phase would allow a drug to rapidly penetrate the skin upon application, and when this pool of solubilized drug was depleted, additional drug could penetrate into the skin from the suspension phase. Based on the tape strip results from the current study it appears that halcinonide, which is manufactured in a biphasic formulation, follows this pattern of penetration and absorption into the stratum corneum. In contrast, fluocinonide appears to exist in a soluble state without much, if any, amount in a suspension phase because it had no sustained release during the 9 hours after application.

Common belief among dermatologists is that long-term use of corticosteroids leads to tachyphylaxis,¹⁴ which can be attributed to poor patient adherence. If patients skip doses, then the steady state of the product at the target site is not maintained. It is interesting to speculate that using agents with more sustained release beyond the time of application (such as halcinonide) may preserve steady-state levels even when patients are neglectful of the next medication application. Corticosteroids that work in 2 phases such as halcinonide may minimize tachyphylaxis experienced with prolonged use of corticosteroids.

Fluocinonide and halcinonide are both class II high-potency corticosteroids as shown on outcomes from vasoconstrictor assays, which assess the extent to which a corticosteroid causes cutaneous vasoconstriction or blanching in normal healthy individuals.¹⁵ The assay depends on the molecule diffusing from the vehicle, penetrating the skin, and causing a reaction (blanching) that is then evaluated. The assay cannot effectively evaluate the rate of continued diffusion and skin penetration beyond the appearance of blanching. In contrast, the tape-stripping method provides an inside look at the extent of penetration of the corticosteroid beyond the skin surface and the rate of its clearance from different skin layers. In the current study, the levels of fluocinonide declined after peaking at 1 hour after application, but the levels of halcinonide clearly remained elevated after peaking at the same time point. Most likely, vasoconstrictor studies would not be able to differentiate between the concentrations of the 2 products in the stratum corneum beyond the first hour after application.

Tape stripping, or dermatopharmacokinetics, has advantages over vasoconstriction assays in studying corticosteroid penetration and clearance from the stratum corneum. At one point, the US Food and Drug Administration had included tape stripping in its preliminary guidelines for generic topical bioequivalence studies until data from the same formulation generated from 2 different laboratories produced different results.¹⁶ Since that time, much work has been done with tape stripping to ensure its consistency. Weigmann et al¹⁷ demonstrated equivalent results with clobetasol using vasoconstriction and tape stripping, and Wiedersberg et al¹⁸ demonstrated the same with betamethasone. For the current study, the fluocinonide and halcinonide formulations were weighed prior to application so that the same dose was tested in all participants. A plunger was used to produce consistent pressure at all application sites to control for the amount of skin that was stripped off with the tape. Results for both corticosteroids were consistent between the participants. Variability in the data was detected; however, this observation is most likely due to the small number of participants in the studies.

Conclusion

In summary, this pilot study demonstrated that fluocinonide concentration in the stratum corneum peaks within the first hour of application before beginning a steady general decline. There was no evidence of sustained release. In contrast, halcin-onide demonstrated a sustained release for 6 hours after application. Halcinonide is formulated in a cream base in which the corticosteroid is present in a solution and suspension phase that allows for sustained delivery in skin over time. Fluocinonide does not appear to be formulated in the same way, and its concentrations in the stratum corneum begin to decline 1 hour after application.

Acknowledgement

Thank you to Robert Kellar, PhD, at the Center for Bioengineering Innovation at Northern Arizona University, Flagstaff, for conducting the liquid chromatography–mass spectrometry.

The active ingredient of any pharmaceutical product is responsible for the agent’s efficacy and safety profile. This ingredient is extensively studied in clinical trials and evaluated by the US Food and Drug Administration before the product is commercially available. In dermatologic products, especially those for treating dermatoses, the vehicle in which the active ingredient is formulated also plays a role in drug delivery and indirectly impacts therapeutic outcomes, unlike excipients in oral medications. Topical vehicles must be stable, provide a suitable environment that will not degrade the active ingredient or affect its efficacy, and be cosmetically acceptable.¹

Topical vehicles are formulated to maintain the stability of the active ingredient and allow it to readily penetrate the skin and reach its target area with minimal absorption into the bloodstream, thus avoiding systemic adverse events. A variety of vehicles can exist for a single active ingredient to accommodate different phases of disease and different anatomical sites where the disease may occur.² For example, alcohol-based vehicles, sprays, and foams are preferred for the scalp where evaporation of the vehicle is beneficial to prevent greasiness of the hair, while ointments may be preferred due to their occlusive nature for areas with xerotic or thick skin from dermatoses.

Cosmetic acceptability of the vehicle may influence patient adherence to therapy. Housman et al³ assessed a variety of products formulated in different vehicles (ie, solutions, foams, emollients, gels, creams, ointments) for the treatment of psoriasis. Patients with psoriasis applied each test product to a quarter-sized area of normal skin on the forearm using a cotton swab and completed a preference questionnaire. By far, respondents significantly preferred solutions and foams over creams, gels, and ointments (P<.01). Side effects were rated to be the most important characteristics of topical therapy, followed by time needed for application, ease of application, and messiness.³ Presumably, if patients are frustrated with the topical product that they are using, adherence to the prescribed dosage and application instructions will diminish over time, leading to suboptimal steady-state levels of the product. If appropriate levels of the drug are not present at the target site, treatment will not be successful.

Steady-state levels of a topical drug at the site of action also are maintained via appropriate application frequency, most commonly once to 4 times daily for dermatologic products. Fluocinonide and halcinonide are class II (potent) corticosteroids indicated for the relief of inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses and usually are administered at least twice daily. In double-blind clinical studies comparing both products in the treatment of psoriasis, halcinonide resulted in more improved outcomes than fluocinonide.^4-6 Sudilovsky and Clewe⁴ studied 140 patients with moderate to severe psoriasis. After 3 weeks of treatment, 44% showed superior results with halcinonide, 27% showed superior results with fluocinonide, 26% showed equal results with both products, and 3% showed no relief.⁴ Similarly, Close⁵ reported that 61% of patients showed superior results with halcinonide, 25% showed superior results with fluocinonide, 10% showed equal results with both products, and 4% showed no relief (N=50). Lynfield and Watsky⁶ reported that 56% of patients with severe psoriasis who were treated with halcinonide for 2 weeks showed improvement to normal or slight inflammation compared to 44% of patients treated with fluocinonide (N=59). All 3 studies used cream formulations of halcinonide and fluocinonide.

Recently, halcinonide cream was shown to have an immediate release into the stratum corneum that peaked within 1 hour of application and remained elevated for 6 hours before beginning to decline.⁷ These results support a biphasic release of halcinonide, which is in agreement with its formulation—that halcinonide exists in both a solution phase for immediate release into the skin and in a suspension phase that allows a sustained release after equilibrium is reached between the solution and suspension phases.⁸ Fluocinonide is not known to be formulated in a similar way. Its vehicle composition and penetration into the skin could explain the superior efficacy of halcinonide versus fluocinonide.

The current pilot study was conducted to compare the release pattern of fluocinonide cream versus halcinonide cream into the stratum corneum using an in vivo, noninvasive method. Results for halcin-onide have been previously published.⁷

Methods

Participants were sequestered in a controlled environment for the entire day to allow the skin to equilibrate prior to product application. The methodology for the application and quantification of halcinonide cream 0.1% into the stratum corneum of 5 participants using a tape-stripping protocol has been described elsewhere.⁷ Concordia Clinical Research institutional review board (Cedar Knolls, New Jersey) approved this study, which was conducted at Dermatology Consulting Services (High Point, North Carolina).

A 0.1-g dose of generic fluocinonide cream 0.05% was applied to four 2.5-cm circular sites on the forearm in 5 participants with normal skin until completely absorbed. Circular tape strips were subsequently placed on the application site at 1, 3, 6, and 9 hours posttreatment and were held for 10 seconds with a controlled pressure plunger to ensure adequate and consistent contact between the tape strip and the skin. The tape strip was removed with forceps, rolled with the skin scale inside, and placed in a glass vial. This procedure was repeated 6 times at 1 of 4 sites with a new tape strip at each time point to obtain samples from deeper skin layers. A total of 24 tape strips were collected from each participant.

All vials were frozen at -20°C and were shipped overnight to Robert Kellar, PhD, at the Center for Bioengineering Innovation at Northern Arizona University (Flagstaff, Arizona) for mass spectroscopy evaluation. Once received at the outside facility, the vials were stored at -20°C until analysis. Each sample was spiked with a known quantity of an appropriate reference standard and extracted with 1 mL acetonitrile at room temperature for 1 minute with agitation. New unused tape strips were spiked with a small amount of fluocinonide reference standard for extraction efficiency.

Extracts were evaporated to dryness under nitrogen gas, resuspended in 200 µL chromatography solvent, and quantified using liquid chromatography–mass spectrometry. To remove the skin scale from the tape strips, 10 mL of a solvent solution of 0.1 mg/mL fludrocortisone acetate in acetonitrile was dispensed into a 4 dram vial containing the tape strip. The vials were ultrasonicated and shaken for 10 to 15 minutes, and the samples were further diluted to 100-fold and were inverted several times to ensure complete dissolution of fluocinonide before liquid chromatography–mass spectrometry.

A standard curve ranging from the lower limit of quantification to the upper limit of quantification for the fluocinonide reference was used to determine the quantity of fluocinonide in each of the tape strips. Once the lower limit of quantification was reached in a given set of tape strip samples (1-, 3-, 6-, and 9-hour samples), the next 2 sequential tape strips in that set were analyzed to confirm fluocinonide was not detectable in deeper layers. Standard quality controls were analyzed to ensure run-to-run and sample-to-sample accuracy.

Each sample was analyzed in duplicate; 10 mg fluocinonide was used as a reference standard. The minimum detectable concentration of fluocinonide was 1 ng/mL.

Results

As expected, tape strip 1 from each participant contained the highest concentration of fluocinonide. This strip corresponded to the most superficial layer of skin. Concentrations decreased in deeper skin layers, as detected in strips 2 to 6.

In general, the average concentration of fluocin-onide in strip 1 for all 5 participants was highest at hour 1, with a subsequent decline at hours 3, 6, and 9; however, participant 1 showed a second peak in fluocinonide concentration at hour 6 (Figure 1). When the fluocinonide concentration in strips 1 to 6 was averaged for each participant at each time point, similar results were obtained: a general decline after hour 1, but a second prominent peak at hour 6 in participant 1 only. In participant 1, the average fluocinonide concentration for strips 1 to 6 was 393 ng/mL at hour 1 and declined to 208 ng/mL at hour 3; it increased to 451 ng/mL at hour 6 before declining again to 202 ng/mL at hour 9.

Figure 1. Fluocinonide concentration in tape strip 1 for all participants (N=5).

Because participant 1 was the only one to exhibit a second peak of fluocinonide concentration, it appears that measurements obtained from this participant may be outliers. When removing partici-pant 1 from the analysis of fluocinonide concentration in strip 1 at each time point, a clear decline is evident from hour 1 to hour 9 (Figure 2A, red line [partici-pants 2–5] vs blue line [participants 1–5]).

When the average concentration of fluocinonide was calculated in strips 1 to 6 from all participants, there was a general steady decline after hour 1 with a slight increase of 25 ng/mL at hour 6 (Figure 2B, blue line). This increase is due to the measurements obtained from participant 1; however, if partici-pant 1 is removed from the analysis, a constant decline is observed from hour 1 to hour 9 (Figure 2B, red line).

Figure 2. Average fluocinonide concentration in tape strip 1 only (A) and strips 1 to 6 (B)(N=5). Error bars indicate standard deviation.

A prior study evaluated the penetration and absorption of halcinonide in the stratum corneum.⁷ In summary, halcinonide concentration peaked at hour 1 following application and remained elevated to hour 6, before beginning a slow decline. The average concentration of halcinonide from all participants in strips 1 to 6 reached 1350 ng/mL at hour 1, remained within 93% to 97% of this level (1253–1303 ng/mL) for the next 5 hours, and declined only 29% from the peak at hour 1 to hour 9 (958 ng/mL)(Figure 3, blue line).⁷ In contrast, the fluocinonide concentration in participants 2 to 5 from the current study reached 190 ng/mL at hour 1 and steadily declined 53% to 89 ng/mL by hour 9 (Figure 3, red line).

Figure 3. Average halcinonide and fluocinonide concentrations in tape strips 1 to 6 (N=5 for both). Adapted from Draelos.7 7

Two participants from the prior halcinonide study also were enrolled in the current fluocinonide study (referred to as participant A and B). In general, halcinonide levels in both participants remained elevated for 6 hours after application and declined 27.5% and 35.5%, respectively, by hour 9 (Figure 4). Participant A experienced a 20.5% dip in halcinonide concentration at hour 3 followed by an increase at hour 6; however, the halcinonide concentration at hour 9 was similar to hour 3.⁷ In contrast, fluocin-onide concentrations for these participants peaked at 1 hour and clearly declined approximately 60% over the next 8 hours.

Figure 4. Fluocinonide and halcin-onide concentrations in tape strips 1 to 6 for 2 participants who received both corticosteroids during different study periods (referred to as participant A and B).

Comment

The release of both fluocinonide and halcinonide into the skin was evaluated using dermal tape stripping on 4 sites on the forearms of healthy individuals. Cream formulations of each corticosteroid were evaluated in 5 participants, with 2 participants receiving both formulations during different study periods. In the prior study with halcinonide, the stratum corneum exhibited the highest concentration of the corticosteroid, with substantial declines beyond strip 6 (ie, strips 7–20).⁷ For this reason, only strips 1 to 6 were evaluated for corticosteroid penetration and absorption.

Results from strip 1 indicated immediate absorption of corticosteroid (fluocinonide and halcinonide) into the skin. Unlike the release of halcinonide, which demonstrated a clear sustained release over 6 hours before decreasing,⁷ fluocinonide concentrations began declining immediately after peaking at hour 1 and continued to decline up to hour 9. Only participant 1 exhibited a second peak of fluocinonide concentration at hour 6; the rest of the participants did not. This second peak is most likely an anomaly due to the small number of participants rather than a true elevation.

Given the rapid decline of fluocinonide concentration over the 9 hours compared with the more gradual decline of halcinonide concentration, there appears to be no evidence of a biphasic sustained release of fluocinonide from its vehicle. This difference in release pattern from each corticosteroid’s respective vehicle may explain in part the different clinical outcomes in comparative studies.^4-6

It is known that vehicle composition affects corticosteroid diffusion from the vehicle to the skin surface and subsequent penetration into the skin.⁹ Either process can determine the overall effectiveness of the product. Ayres and Hooper¹⁰ evaluated the penetration of 4 topical preparations of cortisol. Product 1 delivered 16 times more cortisol to the skin than product 2, 8 times more than product 3, and 3 times more than product 4. Because all the preparations contained cortisol-free alcohol, these differences were attributed to the vehicle in which the cortisol was formulated. Products 1 and 4 both contained 10% urea, but the urea in product 1 was a powder in a cream base and the urea in product 4 was in a stabilizing emulsified base. Product 2 contained a propylene glycol/water base and product 3 was a water-miscible cream.¹⁰

Generic corticosteroid products have been observed in clinical practice and have been shown in vasoconstriction assays to be less and more potent than their brand-name equivalents.^2,11 Vasoconstriction assays are the standard for assessing the potency of topical corticosteroids and predicting their clinical efficacy.² One study reported significant differences in therapeutic effectiveness between generic formulations and their brand-name equivalents.¹² Kenalog cream 0.1% (multiple manufacturers) was significantly more potent than any of the generic triamcinolone creams tested (P<.05); in fact, Kenalog cream 0.025% (multiple manufacturers) was statistically superior to all the generic triamcinolone creams 0.1%. Moreover, Artistocort A ointment 0.1% (Lederele Laboratories) and Valisone cream 0.1% (Schering Corporation) also were more potent than their generics at the same concentration in the same vehicle type.¹² A second study also observed that 2 of 6 generic formulations had significantly less vasoconstriction than their respective brand-name formulations.¹¹ A brand-name betamethasone valerate cream produced significantly greater vasoconstriction than its generic equivalent, and a brand-name betamethasone dipropionate cream produced greater vasoconstriction than one generic and equal vasoconstriction to another generic. Additionally, the vasoconstriction measured with Diprosone was greater than that measured with Diprolene, another brand-name product of betamethasone dipropionate.¹¹ Diprosone and Diprolene differ in their vehicle content. The latter, a class I corticosteroid, contains a modified vehicle high in propylene glycol, whereas the former contains less propylene glycol and thus is classified as a class III corticosteroid. Propylene glycol allows hydrophobic molecules such as corticosteroids to dissolve more fully in the vehicle.¹²

Ostrenga et al¹ studied the solubility of corticosteroids in different vehicles and, as expected, corticosteroids that fully solubilized in the vehicle exhibited better penetration into the skin on assessment with vasoconstriction assays. Corticosteroids in a suspension, on the other hand, showed slower penetration into the skin.^1,13 A balance between the solution and suspension phase would allow a drug to rapidly penetrate the skin upon application, and when this pool of solubilized drug was depleted, additional drug could penetrate into the skin from the suspension phase. Based on the tape strip results from the current study it appears that halcinonide, which is manufactured in a biphasic formulation, follows this pattern of penetration and absorption into the stratum corneum. In contrast, fluocinonide appears to exist in a soluble state without much, if any, amount in a suspension phase because it had no sustained release during the 9 hours after application.

Common belief among dermatologists is that long-term use of corticosteroids leads to tachyphylaxis,¹⁴ which can be attributed to poor patient adherence. If patients skip doses, then the steady state of the product at the target site is not maintained. It is interesting to speculate that using agents with more sustained release beyond the time of application (such as halcinonide) may preserve steady-state levels even when patients are neglectful of the next medication application. Corticosteroids that work in 2 phases such as halcinonide may minimize tachyphylaxis experienced with prolonged use of corticosteroids.

Fluocinonide and halcinonide are both class II high-potency corticosteroids as shown on outcomes from vasoconstrictor assays, which assess the extent to which a corticosteroid causes cutaneous vasoconstriction or blanching in normal healthy individuals.¹⁵ The assay depends on the molecule diffusing from the vehicle, penetrating the skin, and causing a reaction (blanching) that is then evaluated. The assay cannot effectively evaluate the rate of continued diffusion and skin penetration beyond the appearance of blanching. In contrast, the tape-stripping method provides an inside look at the extent of penetration of the corticosteroid beyond the skin surface and the rate of its clearance from different skin layers. In the current study, the levels of fluocinonide declined after peaking at 1 hour after application, but the levels of halcinonide clearly remained elevated after peaking at the same time point. Most likely, vasoconstrictor studies would not be able to differentiate between the concentrations of the 2 products in the stratum corneum beyond the first hour after application.

Tape stripping, or dermatopharmacokinetics, has advantages over vasoconstriction assays in studying corticosteroid penetration and clearance from the stratum corneum. At one point, the US Food and Drug Administration had included tape stripping in its preliminary guidelines for generic topical bioequivalence studies until data from the same formulation generated from 2 different laboratories produced different results.¹⁶ Since that time, much work has been done with tape stripping to ensure its consistency. Weigmann et al¹⁷ demonstrated equivalent results with clobetasol using vasoconstriction and tape stripping, and Wiedersberg et al¹⁸ demonstrated the same with betamethasone. For the current study, the fluocinonide and halcinonide formulations were weighed prior to application so that the same dose was tested in all participants. A plunger was used to produce consistent pressure at all application sites to control for the amount of skin that was stripped off with the tape. Results for both corticosteroids were consistent between the participants. Variability in the data was detected; however, this observation is most likely due to the small number of participants in the studies.

Conclusion

In summary, this pilot study demonstrated that fluocinonide concentration in the stratum corneum peaks within the first hour of application before beginning a steady general decline. There was no evidence of sustained release. In contrast, halcin-onide demonstrated a sustained release for 6 hours after application. Halcinonide is formulated in a cream base in which the corticosteroid is present in a solution and suspension phase that allows for sustained delivery in skin over time. Fluocinonide does not appear to be formulated in the same way, and its concentrations in the stratum corneum begin to decline 1 hour after application.

Acknowledgement

Thank you to Robert Kellar, PhD, at the Center for Bioengineering Innovation at Northern Arizona University, Flagstaff, for conducting the liquid chromatography–mass spectrometry.

Cutaneous North American blastomycosis is a deep fungal infection caused by Blastomyces dermatitidis, a thermally dimorphic fungus that is endemic to the Great Lakes region as well as the Mississippi and Ohio River valleys where it thrives in moist acidic soil enriched with organic material.^1,2 In humans, the annual incidence rate is estimated to be 0.6 cases per million,³ though it may be as high as 42 cases per 100,000 in endemic areas.⁴ Infection typically results from the inhalation of conidia and manifests as either acute or chronic pneumonia.⁵ Most patients with acute disease present with nonspecific flulike symptoms and a nonproductive cough.

Dissemination occurs in approximately 25% of cases,⁶ most commonly affecting the skin. Other potential sites of dissemination include bone, the genitourinary tract, and the central nervous system. Cutaneous lesions, which may be either verrucous or ulcerative plaques, often occur on or around orifices contiguous to the respiratory tract.⁷ Verrucous lesions tend to have an irregular shape with well-defined borders and surface crusting. Ulcerative lesions have heaped-up borders and often have an exudative base.⁸ The differential diagnosis of cutaneous North American blastomycosis lesions includes squamous cell carcinoma, giant keratoacanthoma, verrucae, basal cell carcinoma, scrofuloderma, lupus vulgaris, nocardiosis, syphilis, bromoderma, iododerma, granuloma inguinale, tuberculosis verrucosa cutis, mycetoma, and actinomycosis.^7,8

Although periorificial cutaneous manifestations of disseminated blastomycosis are common, perianal lesions are rare. The differential diagnosis of  perianal verrucous plaques includes condyloma acuminatum, squamous cell carcinoma, adenocarcinoma, Buschke-Löwenstein tumor, actinomycosis, and localized fungal infections such as blastomycosis.⁹

Case Report

A 57-year-old man presented with a palpable perianal mass that produced small amounts of blood in his underwear and on toilet paper. The patient reported no history of hemorrhoids, anoreceptive intercourse, or sexually transmitted disease. Four months prior to presentation, he had a prolonged upper respiratory tract illness with a subjective fever and productive cough of 2 months’ duration. The patient described himself as an avid outdoorsman who worked at a summer resort and spent a great deal of time in the forests of central Wisconsin last autumn. Physical examination revealed a well-demarcated, firm, moist plaque with a verrucous surface that measured 3.5×2.7 cm and extended from the anal verge to the perianal skin (Figure 1).

Figure 1. A well-demarcated, firm, moist plaque with a verrucous surface extended from the anal verge to the perianal skin.

Potassium hydroxide preparation of a biopsy specimen (Figure 2), a punch biopsy of the lesion (Figure 3), and Gomori methenamine-silver staining (Figure 4) revealed scattered yeast spores, some demonstrating broad-based budding, with pseudoepitheliomatous hyperplasia, dermal neutrophils, and intraepithelial microabscesses. The patient’s urine was positive for Blastomyces antigen (1.04 ng/mL). Chest radiography demonstrated a localized infiltrate in the right hilum with possible mass effect. Computed tomography showed a consolidative opacity measuring 4.0×3.4 cm in the upper lobe of the right lung (Figure 5).

Figure 2. A biopsy specimen prepared with potassium hydroxide showed broad-based, figure eight–shaped budding yeast spores above the arrowhead (original magnification ×600).

Figure 3. A punch biopsy of the lesion revealed scattered yeast spores, some demonstrating broad-based budding, with pseudoepitheliomatous hyperplasia and microabscesses (H&E, original magnification ×400).

The patient was diagnosed with cutaneous North American blastomycosis and prescribed a 6-month course of oral itraconazole 200 mg twice daily. At his 3-month follow-up visit, the perianal plaque hadalmost completely resolved (Figure 6). However, because the patient had increasing lower extremity edema, subjective hearing loss, and abnormal liver function tests, itraconazole treatment was discontinued and replaced with oral fluconazole 400 mg daily for the next 3 months. The right hilar mass had visibly improved on follow-up chest radiography 2 months after the patient started antifungal therapy with itraconazole and had resolved within another 3 months of treatment.

Figure 4. Gomori methenamine-silver stain demonstrated broad-based budding yeast (original magnification ×400).

Figure 5. Computed tomography revealed a consolidative opacity measuring 4.0×3.4 cm in the upper lobe of the right lung.

Comment

Cutaneous blastomycosis results most often from the hematogenous spread of B dermatitidis from the lungs and rarely from direct inoculation.^5,10 Skin lesions tend to occur on exposed areas, such as the face, scalp, hands, wrists, feet, and ankles.^7,11-13 Dissemination to the perianal skin is rare, though it has been reported in 2 other patients; both patients, similar to our patient, had evidence of pulmonary involvement at some point in their clinical course.^9,14

Figure 6. The perianal plaque had almost completely resolved after 3 months of oral itraconazole therapy.

Diagnosis is based on identification of  B dermatitidis by microscopy or culture. Potassium hydroxide preparation of biopsy specimens typically shows broad-based budding yeast.¹³ Characteristic findings of histopathologic studies include pseudo-epitheliomatous hyperplasia, intraepidermal abscesses, and a dermal infiltrate of polymorphonuclear  leukocytes.¹⁵ On fungal culture, B dermatitidis is  slow growing and may require a 2- to 4-week incubation period. Serologic tests are available, but sensitivity is low, at 9%, 28%, and 77% for complement fixation, immunodiffusion, and enzyme immunoassay, respectively.¹⁶

Conclusion

North American blastomycosis should be considered in patients who have verrucous or ulcerative perianal lesions and have lived in or traveled to endemic regions, especially if they have recent or ongoing pulmonary symptoms. Potassium hydroxide preparation and fungal staining of biopsy specimens can aid in diagnosis.

Acknowledgment

The authors thank the Marshfield Clinic Research Foundation’s Office of Scientific Writing and Publication (Marshfield, Wisconsin) for editorial assistance in the preparation of  this manuscript.

Cutaneous North American blastomycosis is a deep fungal infection caused by Blastomyces dermatitidis, a thermally dimorphic fungus that is endemic to the Great Lakes region as well as the Mississippi and Ohio River valleys where it thrives in moist acidic soil enriched with organic material.^1,2 In humans, the annual incidence rate is estimated to be 0.6 cases per million,³ though it may be as high as 42 cases per 100,000 in endemic areas.⁴ Infection typically results from the inhalation of conidia and manifests as either acute or chronic pneumonia.⁵ Most patients with acute disease present with nonspecific flulike symptoms and a nonproductive cough.

Dissemination occurs in approximately 25% of cases,⁶ most commonly affecting the skin. Other potential sites of dissemination include bone, the genitourinary tract, and the central nervous system. Cutaneous lesions, which may be either verrucous or ulcerative plaques, often occur on or around orifices contiguous to the respiratory tract.⁷ Verrucous lesions tend to have an irregular shape with well-defined borders and surface crusting. Ulcerative lesions have heaped-up borders and often have an exudative base.⁸ The differential diagnosis of cutaneous North American blastomycosis lesions includes squamous cell carcinoma, giant keratoacanthoma, verrucae, basal cell carcinoma, scrofuloderma, lupus vulgaris, nocardiosis, syphilis, bromoderma, iododerma, granuloma inguinale, tuberculosis verrucosa cutis, mycetoma, and actinomycosis.^7,8

Although periorificial cutaneous manifestations of disseminated blastomycosis are common, perianal lesions are rare. The differential diagnosis of  perianal verrucous plaques includes condyloma acuminatum, squamous cell carcinoma, adenocarcinoma, Buschke-Löwenstein tumor, actinomycosis, and localized fungal infections such as blastomycosis.⁹

Case Report

A 57-year-old man presented with a palpable perianal mass that produced small amounts of blood in his underwear and on toilet paper. The patient reported no history of hemorrhoids, anoreceptive intercourse, or sexually transmitted disease. Four months prior to presentation, he had a prolonged upper respiratory tract illness with a subjective fever and productive cough of 2 months’ duration. The patient described himself as an avid outdoorsman who worked at a summer resort and spent a great deal of time in the forests of central Wisconsin last autumn. Physical examination revealed a well-demarcated, firm, moist plaque with a verrucous surface that measured 3.5×2.7 cm and extended from the anal verge to the perianal skin (Figure 1).

Figure 1. A well-demarcated, firm, moist plaque with a verrucous surface extended from the anal verge to the perianal skin.

Potassium hydroxide preparation of a biopsy specimen (Figure 2), a punch biopsy of the lesion (Figure 3), and Gomori methenamine-silver staining (Figure 4) revealed scattered yeast spores, some demonstrating broad-based budding, with pseudoepitheliomatous hyperplasia, dermal neutrophils, and intraepithelial microabscesses. The patient’s urine was positive for Blastomyces antigen (1.04 ng/mL). Chest radiography demonstrated a localized infiltrate in the right hilum with possible mass effect. Computed tomography showed a consolidative opacity measuring 4.0×3.4 cm in the upper lobe of the right lung (Figure 5).

Figure 2. A biopsy specimen prepared with potassium hydroxide showed broad-based, figure eight–shaped budding yeast spores above the arrowhead (original magnification ×600).

Figure 3. A punch biopsy of the lesion revealed scattered yeast spores, some demonstrating broad-based budding, with pseudoepitheliomatous hyperplasia and microabscesses (H&E, original magnification ×400).

The patient was diagnosed with cutaneous North American blastomycosis and prescribed a 6-month course of oral itraconazole 200 mg twice daily. At his 3-month follow-up visit, the perianal plaque hadalmost completely resolved (Figure 6). However, because the patient had increasing lower extremity edema, subjective hearing loss, and abnormal liver function tests, itraconazole treatment was discontinued and replaced with oral fluconazole 400 mg daily for the next 3 months. The right hilar mass had visibly improved on follow-up chest radiography 2 months after the patient started antifungal therapy with itraconazole and had resolved within another 3 months of treatment.

Figure 4. Gomori methenamine-silver stain demonstrated broad-based budding yeast (original magnification ×400).

Figure 5. Computed tomography revealed a consolidative opacity measuring 4.0×3.4 cm in the upper lobe of the right lung.

Comment

Cutaneous blastomycosis results most often from the hematogenous spread of B dermatitidis from the lungs and rarely from direct inoculation.^5,10 Skin lesions tend to occur on exposed areas, such as the face, scalp, hands, wrists, feet, and ankles.^7,11-13 Dissemination to the perianal skin is rare, though it has been reported in 2 other patients; both patients, similar to our patient, had evidence of pulmonary involvement at some point in their clinical course.^9,14

Figure 6. The perianal plaque had almost completely resolved after 3 months of oral itraconazole therapy.

Diagnosis is based on identification of  B dermatitidis by microscopy or culture. Potassium hydroxide preparation of biopsy specimens typically shows broad-based budding yeast.¹³ Characteristic findings of histopathologic studies include pseudo-epitheliomatous hyperplasia, intraepidermal abscesses, and a dermal infiltrate of polymorphonuclear  leukocytes.¹⁵ On fungal culture, B dermatitidis is  slow growing and may require a 2- to 4-week incubation period. Serologic tests are available, but sensitivity is low, at 9%, 28%, and 77% for complement fixation, immunodiffusion, and enzyme immunoassay, respectively.¹⁶

Conclusion

North American blastomycosis should be considered in patients who have verrucous or ulcerative perianal lesions and have lived in or traveled to endemic regions, especially if they have recent or ongoing pulmonary symptoms. Potassium hydroxide preparation and fungal staining of biopsy specimens can aid in diagnosis.

Acknowledgment

The authors thank the Marshfield Clinic Research Foundation’s Office of Scientific Writing and Publication (Marshfield, Wisconsin) for editorial assistance in the preparation of  this manuscript.

Cutaneous North American blastomycosis is a deep fungal infection caused by Blastomyces dermatitidis, a thermally dimorphic fungus that is endemic to the Great Lakes region as well as the Mississippi and Ohio River valleys where it thrives in moist acidic soil enriched with organic material.^1,2 In humans, the annual incidence rate is estimated to be 0.6 cases per million,³ though it may be as high as 42 cases per 100,000 in endemic areas.⁴ Infection typically results from the inhalation of conidia and manifests as either acute or chronic pneumonia.⁵ Most patients with acute disease present with nonspecific flulike symptoms and a nonproductive cough.

Dissemination occurs in approximately 25% of cases,⁶ most commonly affecting the skin. Other potential sites of dissemination include bone, the genitourinary tract, and the central nervous system. Cutaneous lesions, which may be either verrucous or ulcerative plaques, often occur on or around orifices contiguous to the respiratory tract.⁷ Verrucous lesions tend to have an irregular shape with well-defined borders and surface crusting. Ulcerative lesions have heaped-up borders and often have an exudative base.⁸ The differential diagnosis of cutaneous North American blastomycosis lesions includes squamous cell carcinoma, giant keratoacanthoma, verrucae, basal cell carcinoma, scrofuloderma, lupus vulgaris, nocardiosis, syphilis, bromoderma, iododerma, granuloma inguinale, tuberculosis verrucosa cutis, mycetoma, and actinomycosis.^7,8

Although periorificial cutaneous manifestations of disseminated blastomycosis are common, perianal lesions are rare. The differential diagnosis of  perianal verrucous plaques includes condyloma acuminatum, squamous cell carcinoma, adenocarcinoma, Buschke-Löwenstein tumor, actinomycosis, and localized fungal infections such as blastomycosis.⁹

Case Report

A 57-year-old man presented with a palpable perianal mass that produced small amounts of blood in his underwear and on toilet paper. The patient reported no history of hemorrhoids, anoreceptive intercourse, or sexually transmitted disease. Four months prior to presentation, he had a prolonged upper respiratory tract illness with a subjective fever and productive cough of 2 months’ duration. The patient described himself as an avid outdoorsman who worked at a summer resort and spent a great deal of time in the forests of central Wisconsin last autumn. Physical examination revealed a well-demarcated, firm, moist plaque with a verrucous surface that measured 3.5×2.7 cm and extended from the anal verge to the perianal skin (Figure 1).

Figure 1. A well-demarcated, firm, moist plaque with a verrucous surface extended from the anal verge to the perianal skin.

Potassium hydroxide preparation of a biopsy specimen (Figure 2), a punch biopsy of the lesion (Figure 3), and Gomori methenamine-silver staining (Figure 4) revealed scattered yeast spores, some demonstrating broad-based budding, with pseudoepitheliomatous hyperplasia, dermal neutrophils, and intraepithelial microabscesses. The patient’s urine was positive for Blastomyces antigen (1.04 ng/mL). Chest radiography demonstrated a localized infiltrate in the right hilum with possible mass effect. Computed tomography showed a consolidative opacity measuring 4.0×3.4 cm in the upper lobe of the right lung (Figure 5).

Figure 2. A biopsy specimen prepared with potassium hydroxide showed broad-based, figure eight–shaped budding yeast spores above the arrowhead (original magnification ×600).

Figure 3. A punch biopsy of the lesion revealed scattered yeast spores, some demonstrating broad-based budding, with pseudoepitheliomatous hyperplasia and microabscesses (H&E, original magnification ×400).

The patient was diagnosed with cutaneous North American blastomycosis and prescribed a 6-month course of oral itraconazole 200 mg twice daily. At his 3-month follow-up visit, the perianal plaque hadalmost completely resolved (Figure 6). However, because the patient had increasing lower extremity edema, subjective hearing loss, and abnormal liver function tests, itraconazole treatment was discontinued and replaced with oral fluconazole 400 mg daily for the next 3 months. The right hilar mass had visibly improved on follow-up chest radiography 2 months after the patient started antifungal therapy with itraconazole and had resolved within another 3 months of treatment.

Figure 4. Gomori methenamine-silver stain demonstrated broad-based budding yeast (original magnification ×400).

Figure 5. Computed tomography revealed a consolidative opacity measuring 4.0×3.4 cm in the upper lobe of the right lung.

Comment

Cutaneous blastomycosis results most often from the hematogenous spread of B dermatitidis from the lungs and rarely from direct inoculation.^5,10 Skin lesions tend to occur on exposed areas, such as the face, scalp, hands, wrists, feet, and ankles.^7,11-13 Dissemination to the perianal skin is rare, though it has been reported in 2 other patients; both patients, similar to our patient, had evidence of pulmonary involvement at some point in their clinical course.^9,14

Figure 6. The perianal plaque had almost completely resolved after 3 months of oral itraconazole therapy.

Diagnosis is based on identification of  B dermatitidis by microscopy or culture. Potassium hydroxide preparation of biopsy specimens typically shows broad-based budding yeast.¹³ Characteristic findings of histopathologic studies include pseudo-epitheliomatous hyperplasia, intraepidermal abscesses, and a dermal infiltrate of polymorphonuclear  leukocytes.¹⁵ On fungal culture, B dermatitidis is  slow growing and may require a 2- to 4-week incubation period. Serologic tests are available, but sensitivity is low, at 9%, 28%, and 77% for complement fixation, immunodiffusion, and enzyme immunoassay, respectively.¹⁶

Conclusion

North American blastomycosis should be considered in patients who have verrucous or ulcerative perianal lesions and have lived in or traveled to endemic regions, especially if they have recent or ongoing pulmonary symptoms. Potassium hydroxide preparation and fungal staining of biopsy specimens can aid in diagnosis.

Acknowledgment

The authors thank the Marshfield Clinic Research Foundation’s Office of Scientific Writing and Publication (Marshfield, Wisconsin) for editorial assistance in the preparation of  this manuscript.

To improve patient care and outcomes, leading dermatologists offered their recommendations on top products for sensitive skin. Consideration must be given to:

• Aveeno Eczema Therapy Moisturizing Cream

• Cetaphil Restoraderm

• PRESCRIBEDsolutions Don’t Be So Sensitive Post-Procedure Cleanser

• Rosaliac AR Intense

• Vanicream

Cutis invites readers to send us their recommendations. Skin care products for babies, men’s shaving products, eye creams, and OTC dandruff treatments will be featured in upcoming editions of Cosmetic Corner. Please e-mail your recommendation(s) to the Editorial Office.

Disclaimer: Opinions expressed herein do not necessarily reflect those of Cutis or Frontline Medical Communications Inc. and shall not be used for product endorsement purposes. Any reference made to a specific commercial product does not indicate or imply that Cutis or Frontline Medical Communications Inc. endorses, recommends, or favors the product mentioned. No guarantee is given to the effects of recommended products.

To improve patient care and outcomes, leading dermatologists offered their recommendations on top products for sensitive skin. Consideration must be given to:

• Aveeno Eczema Therapy Moisturizing Cream

• Cetaphil Restoraderm

• PRESCRIBEDsolutions Don’t Be So Sensitive Post-Procedure Cleanser

• Rosaliac AR Intense

• Vanicream

Cutis invites readers to send us their recommendations. Skin care products for babies, men’s shaving products, eye creams, and OTC dandruff treatments will be featured in upcoming editions of Cosmetic Corner. Please e-mail your recommendation(s) to the Editorial Office.

Disclaimer: Opinions expressed herein do not necessarily reflect those of Cutis or Frontline Medical Communications Inc. and shall not be used for product endorsement purposes. Any reference made to a specific commercial product does not indicate or imply that Cutis or Frontline Medical Communications Inc. endorses, recommends, or favors the product mentioned. No guarantee is given to the effects of recommended products.

To improve patient care and outcomes, leading dermatologists offered their recommendations on top products for sensitive skin. Consideration must be given to:

• Aveeno Eczema Therapy Moisturizing Cream

• Cetaphil Restoraderm

• PRESCRIBEDsolutions Don’t Be So Sensitive Post-Procedure Cleanser

• Rosaliac AR Intense

• Vanicream

Cutis invites readers to send us their recommendations. Skin care products for babies, men’s shaving products, eye creams, and OTC dandruff treatments will be featured in upcoming editions of Cosmetic Corner. Please e-mail your recommendation(s) to the Editorial Office.

Disclaimer: Opinions expressed herein do not necessarily reflect those of Cutis or Frontline Medical Communications Inc. and shall not be used for product endorsement purposes. Any reference made to a specific commercial product does not indicate or imply that Cutis or Frontline Medical Communications Inc. endorses, recommends, or favors the product mentioned. No guarantee is given to the effects of recommended products.

Allergic contact dermatitis (ACD) is a common inflammatory skin condition that affects more than 14 million Americans each year.¹ It has been estimated that the economic burden of ACD is nearly $3 billion per year due to school absences, work time lost, and medical expenditures.^1,2 In fact, skin diseases rank second to traumatic injuries as the most common type of occupational disease.³ As dermatology residents, we will encounter many patients with ACD, a potentially debilitating skin condition. In this column, I will discuss the different types of ACD as well as their differential diagnoses and management options according to the American Academy of Allergy, Asthma & Immunology’s updated practice parameter for contact dermatitis.⁴ The 2015 American Contact Dermatitis Society (ACDS) Allergen of the Year and the ACDS’s Contact Allergen Management Program also will be discussed.

Clinical Presentation and Pathophysiology

Allergic contact dermatitis is a widespread skin condition characterized by erythematous and pruritic skin lesions that occur after contact with external stimuli.⁵ It is caused by a type IV, T cell–mediated, delayed hypersensitivity reaction in which a foreign substance comes into contact with the skin and forms an antigen complex that subsequently leads to sensitization. Upon reexposure to the antigen, the sensitized T cells induce an inflammatory cascade causing the skin changes associated with ACD. Clinical presentations of ACD include vesicles and bullae with distinct angles, lines, and borders.⁶

Differential Diagnosis

In contrast to ACD, irritant contact dermatitis (the more common form of contact dermatitis) is a non–immune-modulated skin reaction that occurs when an individual is exposed to a substance that causes irritation and damage to the keratinocytes.^6,7 It can be an acute reaction to a household cleaning product or a chronic reaction to soap if the patient has had exposure to the product for a prolonged period of time.⁷ The clinical presentation of irritant contact dermatitis includes dry and fissured skin with less distinct borders and negative patch test results.⁶

Some other skin diseases that should be considered in the differential diagnosis for suspected ACD include atopic dermatitis, dyshidrotic eczema, inverse psoriasis, latex allergy, palmoplantar psoriasis, scabies, and tinea pedis.⁵ When ACD is suspected, our diagnostic approach as dermatology residents should be based on a combination of the following factors: the clinical features of the skin reaction (eg, morphology, location, symptoms), the patient’s history of exposure to an alleged allergen and lack of exposure after treatment and/or avoidance, patch test results, laboratory test results, and/or histopathologic examination to exclude other disorders with similar clinical features.⁸

Management

Localized acute lesions of ACD can be successfully treated with mid- or high-potency topical steroids such as triamcinolone 0.1% or clobetasol 0.05%. If an extensive area of the skin (>20%) is affected, systemic steroid therapy often is required, generally offering relief within 12 to 24 hours. Caution should be taken when prescribing oral prednisone, such as for poison ivy, as it should be tapered over a few weeks to prevent rebound dermatitis. If treatment fails and the diagnosis or specific allergen remains unknown, patch testing should be performed.^3,5

Updated Practice Parameter

Practice parameters for contact dermatitis were updated in 2015, as commissioned by the Joint Task Force on Practice Parameters, to address recent advances in the field of contact dermatitis and the most recommended methods for diagnosis and management based on the current scientific literature.⁴ Prior to this update, the most recent recommendations were from 2006.³

Since the publication of the original practice parameter, new questions have been addressed related to emerging clinical problems such as preoperative screening and postimplantation patch testing for metal allergy in patients undergoing joint replacement surgery. In the updated practice parameter, statements have been added that more comprehensively address evaluation and management of occupational contact dermatitis.⁴ The potential benefits and limitations of drug patch testing in patients with maculopapular rashes, erythroderma, and nonimmediate cutaneous reactions also have been addressed. New summary statements have been included that make recommendations on the management of ACD, particularly avoidance and prevention.⁴

ACDS Allergen of the Year

The purpose of this “award” is to recognize the agents that cause the most remarkable clinical effects, those that draw less attention, or those that exhibit exposure patterns that have changed. The ACDS’s 2015 Allergen of the Year is formaldehyde, an inexpensive biocidal preservative used in a wide range of products such as tissue specimen and cadaveric preservation solutions, nail polish, hair-smoothing treatments, and wrinkle-free fabrics.⁹

Formaldehyde-releasing preservatives (FRPs) are among the leading contact allergens and are found in many personal hygiene products, medications, and household cleansers.⁸ Specific sources of FRPs include shampoos, bodywashes, hand soaps, lotions, creams, baby wipes, mascara, disinfectants, fabric softeners, topical wart remedies, adhesives, and tissue specimen preservation solutions.^10-13 According to de Groot et al,¹⁴ the US Food and Drug Administration’s Voluntary Cosmetic Registration Program database has estimated that approximately 20% of personal hygiene products and cosmetics contain an FRP, with imidazolidinyl urea as the most common.

It is important for patients to be aware of sources of formaldehyde exposure and understand that many products containing formaldehyde or FRPs may not list this information on their labels. In fact, one study reported that 33% of 67 moisturizers evaluated did not have proper labeling with regard to their formaldehyde/FRP content.¹⁵

Contact Allergen Management Program

During medical school I served as the Dermatology Interest Group Contact Dermatitis Awareness Chair at the University of Texas Medical Branch (Galveston, Texas) and was fortunate to have attended the annual meeting of the ACDS where I learned about the ACDS Contact Allergen Management Program (CAMP), an online resource for dermatologists to access that provides patients a printout list of allergen and cross-reactivity information for more than 1200 products (http://www.contactderm.org/i4a/pages/indexcfm?pageID=3489). This information helps consumers to choose the right products based on their allergies.

Final Thoughts

A thorough review of a patient’s medical history and, if needed, skin patch testing can identify the responsible allergen and initiate an appropriate avoidance plan for the patient. With appropriate avoidance, patients can achieve resolution of their dermatitis and prevent further episodes to substantially improve their quality of life and decrease health care costs.¹ If left untreated, ACD can evolve from an acute form to a subacute form and eventually chronic eczematous dermatitis or progression to systemic disease.^16,17 Allergic contact dermatitis can negatively impact an individual’s health-related quality of life, particularly in social functioning and psychological well-being.^18,19 Therefore, it is pertinent in our role as dermatology residents to recognize ACD before its progression to a chronic state.

Allergic contact dermatitis (ACD) is a common inflammatory skin condition that affects more than 14 million Americans each year.¹ It has been estimated that the economic burden of ACD is nearly $3 billion per year due to school absences, work time lost, and medical expenditures.^1,2 In fact, skin diseases rank second to traumatic injuries as the most common type of occupational disease.³ As dermatology residents, we will encounter many patients with ACD, a potentially debilitating skin condition. In this column, I will discuss the different types of ACD as well as their differential diagnoses and management options according to the American Academy of Allergy, Asthma & Immunology’s updated practice parameter for contact dermatitis.⁴ The 2015 American Contact Dermatitis Society (ACDS) Allergen of the Year and the ACDS’s Contact Allergen Management Program also will be discussed.

Clinical Presentation and Pathophysiology

Allergic contact dermatitis is a widespread skin condition characterized by erythematous and pruritic skin lesions that occur after contact with external stimuli.⁵ It is caused by a type IV, T cell–mediated, delayed hypersensitivity reaction in which a foreign substance comes into contact with the skin and forms an antigen complex that subsequently leads to sensitization. Upon reexposure to the antigen, the sensitized T cells induce an inflammatory cascade causing the skin changes associated with ACD. Clinical presentations of ACD include vesicles and bullae with distinct angles, lines, and borders.⁶

Differential Diagnosis

In contrast to ACD, irritant contact dermatitis (the more common form of contact dermatitis) is a non–immune-modulated skin reaction that occurs when an individual is exposed to a substance that causes irritation and damage to the keratinocytes.^6,7 It can be an acute reaction to a household cleaning product or a chronic reaction to soap if the patient has had exposure to the product for a prolonged period of time.⁷ The clinical presentation of irritant contact dermatitis includes dry and fissured skin with less distinct borders and negative patch test results.⁶

Some other skin diseases that should be considered in the differential diagnosis for suspected ACD include atopic dermatitis, dyshidrotic eczema, inverse psoriasis, latex allergy, palmoplantar psoriasis, scabies, and tinea pedis.⁵ When ACD is suspected, our diagnostic approach as dermatology residents should be based on a combination of the following factors: the clinical features of the skin reaction (eg, morphology, location, symptoms), the patient’s history of exposure to an alleged allergen and lack of exposure after treatment and/or avoidance, patch test results, laboratory test results, and/or histopathologic examination to exclude other disorders with similar clinical features.⁸

Management

Localized acute lesions of ACD can be successfully treated with mid- or high-potency topical steroids such as triamcinolone 0.1% or clobetasol 0.05%. If an extensive area of the skin (>20%) is affected, systemic steroid therapy often is required, generally offering relief within 12 to 24 hours. Caution should be taken when prescribing oral prednisone, such as for poison ivy, as it should be tapered over a few weeks to prevent rebound dermatitis. If treatment fails and the diagnosis or specific allergen remains unknown, patch testing should be performed.^3,5

Updated Practice Parameter

Practice parameters for contact dermatitis were updated in 2015, as commissioned by the Joint Task Force on Practice Parameters, to address recent advances in the field of contact dermatitis and the most recommended methods for diagnosis and management based on the current scientific literature.⁴ Prior to this update, the most recent recommendations were from 2006.³

Since the publication of the original practice parameter, new questions have been addressed related to emerging clinical problems such as preoperative screening and postimplantation patch testing for metal allergy in patients undergoing joint replacement surgery. In the updated practice parameter, statements have been added that more comprehensively address evaluation and management of occupational contact dermatitis.⁴ The potential benefits and limitations of drug patch testing in patients with maculopapular rashes, erythroderma, and nonimmediate cutaneous reactions also have been addressed. New summary statements have been included that make recommendations on the management of ACD, particularly avoidance and prevention.⁴

ACDS Allergen of the Year

The purpose of this “award” is to recognize the agents that cause the most remarkable clinical effects, those that draw less attention, or those that exhibit exposure patterns that have changed. The ACDS’s 2015 Allergen of the Year is formaldehyde, an inexpensive biocidal preservative used in a wide range of products such as tissue specimen and cadaveric preservation solutions, nail polish, hair-smoothing treatments, and wrinkle-free fabrics.⁹

Formaldehyde-releasing preservatives (FRPs) are among the leading contact allergens and are found in many personal hygiene products, medications, and household cleansers.⁸ Specific sources of FRPs include shampoos, bodywashes, hand soaps, lotions, creams, baby wipes, mascara, disinfectants, fabric softeners, topical wart remedies, adhesives, and tissue specimen preservation solutions.^10-13 According to de Groot et al,¹⁴ the US Food and Drug Administration’s Voluntary Cosmetic Registration Program database has estimated that approximately 20% of personal hygiene products and cosmetics contain an FRP, with imidazolidinyl urea as the most common.

It is important for patients to be aware of sources of formaldehyde exposure and understand that many products containing formaldehyde or FRPs may not list this information on their labels. In fact, one study reported that 33% of 67 moisturizers evaluated did not have proper labeling with regard to their formaldehyde/FRP content.¹⁵

Contact Allergen Management Program

During medical school I served as the Dermatology Interest Group Contact Dermatitis Awareness Chair at the University of Texas Medical Branch (Galveston, Texas) and was fortunate to have attended the annual meeting of the ACDS where I learned about the ACDS Contact Allergen Management Program (CAMP), an online resource for dermatologists to access that provides patients a printout list of allergen and cross-reactivity information for more than 1200 products (http://www.contactderm.org/i4a/pages/indexcfm?pageID=3489). This information helps consumers to choose the right products based on their allergies.

Final Thoughts

A thorough review of a patient’s medical history and, if needed, skin patch testing can identify the responsible allergen and initiate an appropriate avoidance plan for the patient. With appropriate avoidance, patients can achieve resolution of their dermatitis and prevent further episodes to substantially improve their quality of life and decrease health care costs.¹ If left untreated, ACD can evolve from an acute form to a subacute form and eventually chronic eczematous dermatitis or progression to systemic disease.^16,17 Allergic contact dermatitis can negatively impact an individual’s health-related quality of life, particularly in social functioning and psychological well-being.^18,19 Therefore, it is pertinent in our role as dermatology residents to recognize ACD before its progression to a chronic state.

Allergic contact dermatitis (ACD) is a common inflammatory skin condition that affects more than 14 million Americans each year.¹ It has been estimated that the economic burden of ACD is nearly $3 billion per year due to school absences, work time lost, and medical expenditures.^1,2 In fact, skin diseases rank second to traumatic injuries as the most common type of occupational disease.³ As dermatology residents, we will encounter many patients with ACD, a potentially debilitating skin condition. In this column, I will discuss the different types of ACD as well as their differential diagnoses and management options according to the American Academy of Allergy, Asthma & Immunology’s updated practice parameter for contact dermatitis.⁴ The 2015 American Contact Dermatitis Society (ACDS) Allergen of the Year and the ACDS’s Contact Allergen Management Program also will be discussed.

Clinical Presentation and Pathophysiology

Allergic contact dermatitis is a widespread skin condition characterized by erythematous and pruritic skin lesions that occur after contact with external stimuli.⁵ It is caused by a type IV, T cell–mediated, delayed hypersensitivity reaction in which a foreign substance comes into contact with the skin and forms an antigen complex that subsequently leads to sensitization. Upon reexposure to the antigen, the sensitized T cells induce an inflammatory cascade causing the skin changes associated with ACD. Clinical presentations of ACD include vesicles and bullae with distinct angles, lines, and borders.⁶

Differential Diagnosis

In contrast to ACD, irritant contact dermatitis (the more common form of contact dermatitis) is a non–immune-modulated skin reaction that occurs when an individual is exposed to a substance that causes irritation and damage to the keratinocytes.^6,7 It can be an acute reaction to a household cleaning product or a chronic reaction to soap if the patient has had exposure to the product for a prolonged period of time.⁷ The clinical presentation of irritant contact dermatitis includes dry and fissured skin with less distinct borders and negative patch test results.⁶

Some other skin diseases that should be considered in the differential diagnosis for suspected ACD include atopic dermatitis, dyshidrotic eczema, inverse psoriasis, latex allergy, palmoplantar psoriasis, scabies, and tinea pedis.⁵ When ACD is suspected, our diagnostic approach as dermatology residents should be based on a combination of the following factors: the clinical features of the skin reaction (eg, morphology, location, symptoms), the patient’s history of exposure to an alleged allergen and lack of exposure after treatment and/or avoidance, patch test results, laboratory test results, and/or histopathologic examination to exclude other disorders with similar clinical features.⁸

Management

Localized acute lesions of ACD can be successfully treated with mid- or high-potency topical steroids such as triamcinolone 0.1% or clobetasol 0.05%. If an extensive area of the skin (>20%) is affected, systemic steroid therapy often is required, generally offering relief within 12 to 24 hours. Caution should be taken when prescribing oral prednisone, such as for poison ivy, as it should be tapered over a few weeks to prevent rebound dermatitis. If treatment fails and the diagnosis or specific allergen remains unknown, patch testing should be performed.^3,5

Updated Practice Parameter

Practice parameters for contact dermatitis were updated in 2015, as commissioned by the Joint Task Force on Practice Parameters, to address recent advances in the field of contact dermatitis and the most recommended methods for diagnosis and management based on the current scientific literature.⁴ Prior to this update, the most recent recommendations were from 2006.³

Since the publication of the original practice parameter, new questions have been addressed related to emerging clinical problems such as preoperative screening and postimplantation patch testing for metal allergy in patients undergoing joint replacement surgery. In the updated practice parameter, statements have been added that more comprehensively address evaluation and management of occupational contact dermatitis.⁴ The potential benefits and limitations of drug patch testing in patients with maculopapular rashes, erythroderma, and nonimmediate cutaneous reactions also have been addressed. New summary statements have been included that make recommendations on the management of ACD, particularly avoidance and prevention.⁴

ACDS Allergen of the Year

The purpose of this “award” is to recognize the agents that cause the most remarkable clinical effects, those that draw less attention, or those that exhibit exposure patterns that have changed. The ACDS’s 2015 Allergen of the Year is formaldehyde, an inexpensive biocidal preservative used in a wide range of products such as tissue specimen and cadaveric preservation solutions, nail polish, hair-smoothing treatments, and wrinkle-free fabrics.⁹

Formaldehyde-releasing preservatives (FRPs) are among the leading contact allergens and are found in many personal hygiene products, medications, and household cleansers.⁸ Specific sources of FRPs include shampoos, bodywashes, hand soaps, lotions, creams, baby wipes, mascara, disinfectants, fabric softeners, topical wart remedies, adhesives, and tissue specimen preservation solutions.^10-13 According to de Groot et al,¹⁴ the US Food and Drug Administration’s Voluntary Cosmetic Registration Program database has estimated that approximately 20% of personal hygiene products and cosmetics contain an FRP, with imidazolidinyl urea as the most common.

It is important for patients to be aware of sources of formaldehyde exposure and understand that many products containing formaldehyde or FRPs may not list this information on their labels. In fact, one study reported that 33% of 67 moisturizers evaluated did not have proper labeling with regard to their formaldehyde/FRP content.¹⁵

Contact Allergen Management Program

During medical school I served as the Dermatology Interest Group Contact Dermatitis Awareness Chair at the University of Texas Medical Branch (Galveston, Texas) and was fortunate to have attended the annual meeting of the ACDS where I learned about the ACDS Contact Allergen Management Program (CAMP), an online resource for dermatologists to access that provides patients a printout list of allergen and cross-reactivity information for more than 1200 products (http://www.contactderm.org/i4a/pages/indexcfm?pageID=3489). This information helps consumers to choose the right products based on their allergies.

Final Thoughts

A thorough review of a patient’s medical history and, if needed, skin patch testing can identify the responsible allergen and initiate an appropriate avoidance plan for the patient. With appropriate avoidance, patients can achieve resolution of their dermatitis and prevent further episodes to substantially improve their quality of life and decrease health care costs.¹ If left untreated, ACD can evolve from an acute form to a subacute form and eventually chronic eczematous dermatitis or progression to systemic disease.^16,17 Allergic contact dermatitis can negatively impact an individual’s health-related quality of life, particularly in social functioning and psychological well-being.^18,19 Therefore, it is pertinent in our role as dermatology residents to recognize ACD before its progression to a chronic state.

To the Editor:

Nephrogenic systemic fibrosis (NSF) is an emerging medical entity in patients with renal disease, which results in progressive cutaneous and systemic fibrosis. It is a rare disorder that has been recognized in patients with renal impairment since 2000.¹ Patients with NSF demonstrate symmetric dermal and subcutaneous fibrosis evidenced by increasing skin induration on clinical examination. Nephrogenic systemic fibrosis most commonly involves the lower extremities, and after extending to the upper extremities and trunk, it sporadically involves the head and neck.

The clinical manifestation of NSF begins with edema, followed by marked dermal induration, sclerotic plaques, and joint contractures that can lead to considerable disability. Pathogenesis remains to be elucidated; it has been hypothesized that it could be related to gadolinium (Gd). Currently, there is no treatment of this unremitting disease.^1-3 We report the case of a patient affected by NSF after administration of Gd for magnetic resonance angiography.

A 56-year-old woman was referred to the department of dermatology at the University of Maryland (Baltimore, Maryland) with persistent swelling of the lower legs, forearms, and trunk of 5 months’ duration. She had end-stage renal disease of nonspecific origin. Five months prior to presentation, she had magnetic resonance angiography, during which 10 mmol of Gd was administered. After, she developed a persistent rash and swelling of the lower legs. On presentation, physical examination revealed symmetric, shiny, pigmented papules and plaques on the forearms, buttocks, thighs, and legs, with no facial involvement (Figure).

Symmetric pigmented papules and plaques on the right shoulder.

A skin biopsy of thigh lesions showed a diffuse dermal proliferation of bland spindle cells associated with dermal fibrosis. A CD4⁺ cellular infiltrate showed extension into the subcutaneous tissue. Deposition of Gd also was noted in the skin. She was treated with corticosteroid therapy, and after 2 months she reported softening of the affected skin. On 6-month follow-up, her skin lesions did not progress and there was no evidence of systemic involvement. Additionally, renal function had improved.

Nephrogenic systemic fibrosis, also known as nephrogenic fibrosing dermopathy, was first described by Cowper et al¹ in 2000. Since then, more than 215 cases have been reported in the literature. Clinically, it is characterized by acute onset of cutaneous hardening and thickening of the extremities and the trunk, often resulting in flexion contractures. There may be varying surface changes such as pigmentation, peau d’orange texture, and shiny sclerosis. Patients often experience unpleasant symptoms such as pain, pruritus, stiffness, and paresthesia. Systemic involvement has been documented in the heart, lung, tendons, muscle, testes, and lamina dura.^1-4

Histologic findings of NSF are diffuse dermal fibrosis with increased cellular infiltrates comprised of bland spindled fibrocytes. These fibrocytes express CD34 and type I procollagen. Collagen bundles are thickened but retain clefting, and elastic fibers often are prominent. This fibrotic pattern typically extends to the subcutaneous fat septa, which are widened and collagenous. The epidermis generally is uninvolved. Other findings include dermal mucin deposition, calcification of collagen and vessels, increased CD68⁺ histiocytes, increased factor XIIIa and dendritic cells, and neoangiogenesis. Rarely, multinucleated giant cells and Miescher radial granulomas with lymphocytic aggregates mimicking erythema nodosum have been described.^2-4

Dermatologic entities with similar clinical and histopathologic features, including scleroderma, scleromyxedema, lipodermatosclerosis, erythema nodosum, eosinophilic fasciitis, and spindle cell neoplasms, should be excluded.^1-4 The exact pathogenetic mechanisms of NSF have yet to be determined, but there is strong evidence that Gd plays an important causative role.¹ In fact, almost all patients with NSF have been exposed to Gd. Gadolinium has been documented in affected skin of patients with NSF and has been shown to induce NSF-like changes in rat models.

Other clinical factors that have been associated with NSF include erythropoietin, elevated serum calcium and phosphate levels, vascular injury or surgery, iron metabolic abnormalities, and metabolic acidosis. It is likely that many factors in the unique physiologic state of patients with renal failure contribute to the abnormal fibrotic reaction to Gd-containing contrast agents in NSF. Gadolinium is a member of a group of 15 elemental metals termed lanthanoids and has been used extensively worldwide in magnetic resonance imaging as a component of intravenously administered contrast agents. Currently, 6 such agents are approved for use in the United States: gadopentetate dimeglumine, gadoteridol, gadodiamide, gadoversetamide, gadobenate dimeglumine, and gadoxetate sodium. All are chelated Gd products, with the chelate serving to prevent toxicity from free Gd ions.

In patients with no renal function abnormalities, the biologic half-life of Gd-based magnetic resonance contrast agents (GBCAs) is 1.5 to 2.0 hours. However, in patients with abnormal kidney function, this half-life is inversely prolonged, proportional to the glomerular filtration rate.^5-7 The link between GBCA administration and NSF is compelling, though other etiologic associations have been reported. Surgical or vascular procedures, history of a hypercoagulable state, erythropoietin administration, and immune suppression have been proposed as triggering factors in NSF. The proposed mechanisms responsible for fibrosis in NSF have centered on a collagen-producing cell in the peripheral blood termed the circulating fibrocyte. These cells express CD34 and CD45RO antigens and are capable of producing type I collagen.

Circulating fibrocytes traffic to areas of chronic antigenic stimulation promoting wound repair and fibrotic reactions. Some authors have proposed that materials deposited in the skin might serve as targets for circulating fibrocytes.⁸ Circulating fibrocytes also are known to produce inflammatory cytokines including IL-1 and chemokines such as platelet-derived growth factor, transforming growth factor b, and others capable of propagating fibrotic responses. Increased expression of transforming growth factor has been reported in dendritic cells in NSF lesions and Parsons et al⁹ postulated that transglutaminase-2 activation of this protein may be responsible for inciting fibrosis in NSF. Transglutaminases also are known to be directly activated by Gd.^10,11

Transmetalation has been proposed as a possible operative phenomenon responsible for NSF. Several cations including zinc, copper, iron, and carbon are known to compete with Gd and may displace it from the ligand, with anions such as OHe, PO4 3e, and CO3 2e binding the resultant free Gd. Some GBCAs contain excess ligand to diminish potential free Gd concentrations. In fact, substantial elevations of serum calcium and phosphorus in patients with NSF have been noted in a large series of patients with NSF. Calciphylaxis, an often catastrophic condition arising in patients with renal failure, has been described in association with NSF, and sodium thiosulfate has been used with success in treating both conditions.¹⁰ In addition, Sanyal et al¹² noted a substantially higher serum calcium in NSF cases compared with controls.

Gadolinium plays an important role in the pathology of NSF and is confirmed by the presence of Gd in skin biopsies.

To the Editor:

Nephrogenic systemic fibrosis (NSF) is an emerging medical entity in patients with renal disease, which results in progressive cutaneous and systemic fibrosis. It is a rare disorder that has been recognized in patients with renal impairment since 2000.¹ Patients with NSF demonstrate symmetric dermal and subcutaneous fibrosis evidenced by increasing skin induration on clinical examination. Nephrogenic systemic fibrosis most commonly involves the lower extremities, and after extending to the upper extremities and trunk, it sporadically involves the head and neck.

The clinical manifestation of NSF begins with edema, followed by marked dermal induration, sclerotic plaques, and joint contractures that can lead to considerable disability. Pathogenesis remains to be elucidated; it has been hypothesized that it could be related to gadolinium (Gd). Currently, there is no treatment of this unremitting disease.^1-3 We report the case of a patient affected by NSF after administration of Gd for magnetic resonance angiography.

A 56-year-old woman was referred to the department of dermatology at the University of Maryland (Baltimore, Maryland) with persistent swelling of the lower legs, forearms, and trunk of 5 months’ duration. She had end-stage renal disease of nonspecific origin. Five months prior to presentation, she had magnetic resonance angiography, during which 10 mmol of Gd was administered. After, she developed a persistent rash and swelling of the lower legs. On presentation, physical examination revealed symmetric, shiny, pigmented papules and plaques on the forearms, buttocks, thighs, and legs, with no facial involvement (Figure).

Symmetric pigmented papules and plaques on the right shoulder.

A skin biopsy of thigh lesions showed a diffuse dermal proliferation of bland spindle cells associated with dermal fibrosis. A CD4⁺ cellular infiltrate showed extension into the subcutaneous tissue. Deposition of Gd also was noted in the skin. She was treated with corticosteroid therapy, and after 2 months she reported softening of the affected skin. On 6-month follow-up, her skin lesions did not progress and there was no evidence of systemic involvement. Additionally, renal function had improved.

Nephrogenic systemic fibrosis, also known as nephrogenic fibrosing dermopathy, was first described by Cowper et al¹ in 2000. Since then, more than 215 cases have been reported in the literature. Clinically, it is characterized by acute onset of cutaneous hardening and thickening of the extremities and the trunk, often resulting in flexion contractures. There may be varying surface changes such as pigmentation, peau d’orange texture, and shiny sclerosis. Patients often experience unpleasant symptoms such as pain, pruritus, stiffness, and paresthesia. Systemic involvement has been documented in the heart, lung, tendons, muscle, testes, and lamina dura.^1-4

Histologic findings of NSF are diffuse dermal fibrosis with increased cellular infiltrates comprised of bland spindled fibrocytes. These fibrocytes express CD34 and type I procollagen. Collagen bundles are thickened but retain clefting, and elastic fibers often are prominent. This fibrotic pattern typically extends to the subcutaneous fat septa, which are widened and collagenous. The epidermis generally is uninvolved. Other findings include dermal mucin deposition, calcification of collagen and vessels, increased CD68⁺ histiocytes, increased factor XIIIa and dendritic cells, and neoangiogenesis. Rarely, multinucleated giant cells and Miescher radial granulomas with lymphocytic aggregates mimicking erythema nodosum have been described.^2-4

Dermatologic entities with similar clinical and histopathologic features, including scleroderma, scleromyxedema, lipodermatosclerosis, erythema nodosum, eosinophilic fasciitis, and spindle cell neoplasms, should be excluded.^1-4 The exact pathogenetic mechanisms of NSF have yet to be determined, but there is strong evidence that Gd plays an important causative role.¹ In fact, almost all patients with NSF have been exposed to Gd. Gadolinium has been documented in affected skin of patients with NSF and has been shown to induce NSF-like changes in rat models.

Other clinical factors that have been associated with NSF include erythropoietin, elevated serum calcium and phosphate levels, vascular injury or surgery, iron metabolic abnormalities, and metabolic acidosis. It is likely that many factors in the unique physiologic state of patients with renal failure contribute to the abnormal fibrotic reaction to Gd-containing contrast agents in NSF. Gadolinium is a member of a group of 15 elemental metals termed lanthanoids and has been used extensively worldwide in magnetic resonance imaging as a component of intravenously administered contrast agents. Currently, 6 such agents are approved for use in the United States: gadopentetate dimeglumine, gadoteridol, gadodiamide, gadoversetamide, gadobenate dimeglumine, and gadoxetate sodium. All are chelated Gd products, with the chelate serving to prevent toxicity from free Gd ions.

In patients with no renal function abnormalities, the biologic half-life of Gd-based magnetic resonance contrast agents (GBCAs) is 1.5 to 2.0 hours. However, in patients with abnormal kidney function, this half-life is inversely prolonged, proportional to the glomerular filtration rate.^5-7 The link between GBCA administration and NSF is compelling, though other etiologic associations have been reported. Surgical or vascular procedures, history of a hypercoagulable state, erythropoietin administration, and immune suppression have been proposed as triggering factors in NSF. The proposed mechanisms responsible for fibrosis in NSF have centered on a collagen-producing cell in the peripheral blood termed the circulating fibrocyte. These cells express CD34 and CD45RO antigens and are capable of producing type I collagen.

Circulating fibrocytes traffic to areas of chronic antigenic stimulation promoting wound repair and fibrotic reactions. Some authors have proposed that materials deposited in the skin might serve as targets for circulating fibrocytes.⁸ Circulating fibrocytes also are known to produce inflammatory cytokines including IL-1 and chemokines such as platelet-derived growth factor, transforming growth factor b, and others capable of propagating fibrotic responses. Increased expression of transforming growth factor has been reported in dendritic cells in NSF lesions and Parsons et al⁹ postulated that transglutaminase-2 activation of this protein may be responsible for inciting fibrosis in NSF. Transglutaminases also are known to be directly activated by Gd.^10,11

Transmetalation has been proposed as a possible operative phenomenon responsible for NSF. Several cations including zinc, copper, iron, and carbon are known to compete with Gd and may displace it from the ligand, with anions such as OHe, PO4 3e, and CO3 2e binding the resultant free Gd. Some GBCAs contain excess ligand to diminish potential free Gd concentrations. In fact, substantial elevations of serum calcium and phosphorus in patients with NSF have been noted in a large series of patients with NSF. Calciphylaxis, an often catastrophic condition arising in patients with renal failure, has been described in association with NSF, and sodium thiosulfate has been used with success in treating both conditions.¹⁰ In addition, Sanyal et al¹² noted a substantially higher serum calcium in NSF cases compared with controls.

Gadolinium plays an important role in the pathology of NSF and is confirmed by the presence of Gd in skin biopsies.

To the Editor:

Nephrogenic systemic fibrosis (NSF) is an emerging medical entity in patients with renal disease, which results in progressive cutaneous and systemic fibrosis. It is a rare disorder that has been recognized in patients with renal impairment since 2000.¹ Patients with NSF demonstrate symmetric dermal and subcutaneous fibrosis evidenced by increasing skin induration on clinical examination. Nephrogenic systemic fibrosis most commonly involves the lower extremities, and after extending to the upper extremities and trunk, it sporadically involves the head and neck.

The clinical manifestation of NSF begins with edema, followed by marked dermal induration, sclerotic plaques, and joint contractures that can lead to considerable disability. Pathogenesis remains to be elucidated; it has been hypothesized that it could be related to gadolinium (Gd). Currently, there is no treatment of this unremitting disease.^1-3 We report the case of a patient affected by NSF after administration of Gd for magnetic resonance angiography.

A 56-year-old woman was referred to the department of dermatology at the University of Maryland (Baltimore, Maryland) with persistent swelling of the lower legs, forearms, and trunk of 5 months’ duration. She had end-stage renal disease of nonspecific origin. Five months prior to presentation, she had magnetic resonance angiography, during which 10 mmol of Gd was administered. After, she developed a persistent rash and swelling of the lower legs. On presentation, physical examination revealed symmetric, shiny, pigmented papules and plaques on the forearms, buttocks, thighs, and legs, with no facial involvement (Figure).

Symmetric pigmented papules and plaques on the right shoulder.

A skin biopsy of thigh lesions showed a diffuse dermal proliferation of bland spindle cells associated with dermal fibrosis. A CD4⁺ cellular infiltrate showed extension into the subcutaneous tissue. Deposition of Gd also was noted in the skin. She was treated with corticosteroid therapy, and after 2 months she reported softening of the affected skin. On 6-month follow-up, her skin lesions did not progress and there was no evidence of systemic involvement. Additionally, renal function had improved.

Nephrogenic systemic fibrosis, also known as nephrogenic fibrosing dermopathy, was first described by Cowper et al¹ in 2000. Since then, more than 215 cases have been reported in the literature. Clinically, it is characterized by acute onset of cutaneous hardening and thickening of the extremities and the trunk, often resulting in flexion contractures. There may be varying surface changes such as pigmentation, peau d’orange texture, and shiny sclerosis. Patients often experience unpleasant symptoms such as pain, pruritus, stiffness, and paresthesia. Systemic involvement has been documented in the heart, lung, tendons, muscle, testes, and lamina dura.^1-4

Histologic findings of NSF are diffuse dermal fibrosis with increased cellular infiltrates comprised of bland spindled fibrocytes. These fibrocytes express CD34 and type I procollagen. Collagen bundles are thickened but retain clefting, and elastic fibers often are prominent. This fibrotic pattern typically extends to the subcutaneous fat septa, which are widened and collagenous. The epidermis generally is uninvolved. Other findings include dermal mucin deposition, calcification of collagen and vessels, increased CD68⁺ histiocytes, increased factor XIIIa and dendritic cells, and neoangiogenesis. Rarely, multinucleated giant cells and Miescher radial granulomas with lymphocytic aggregates mimicking erythema nodosum have been described.^2-4

Dermatologic entities with similar clinical and histopathologic features, including scleroderma, scleromyxedema, lipodermatosclerosis, erythema nodosum, eosinophilic fasciitis, and spindle cell neoplasms, should be excluded.^1-4 The exact pathogenetic mechanisms of NSF have yet to be determined, but there is strong evidence that Gd plays an important causative role.¹ In fact, almost all patients with NSF have been exposed to Gd. Gadolinium has been documented in affected skin of patients with NSF and has been shown to induce NSF-like changes in rat models.

Other clinical factors that have been associated with NSF include erythropoietin, elevated serum calcium and phosphate levels, vascular injury or surgery, iron metabolic abnormalities, and metabolic acidosis. It is likely that many factors in the unique physiologic state of patients with renal failure contribute to the abnormal fibrotic reaction to Gd-containing contrast agents in NSF. Gadolinium is a member of a group of 15 elemental metals termed lanthanoids and has been used extensively worldwide in magnetic resonance imaging as a component of intravenously administered contrast agents. Currently, 6 such agents are approved for use in the United States: gadopentetate dimeglumine, gadoteridol, gadodiamide, gadoversetamide, gadobenate dimeglumine, and gadoxetate sodium. All are chelated Gd products, with the chelate serving to prevent toxicity from free Gd ions.

In patients with no renal function abnormalities, the biologic half-life of Gd-based magnetic resonance contrast agents (GBCAs) is 1.5 to 2.0 hours. However, in patients with abnormal kidney function, this half-life is inversely prolonged, proportional to the glomerular filtration rate.^5-7 The link between GBCA administration and NSF is compelling, though other etiologic associations have been reported. Surgical or vascular procedures, history of a hypercoagulable state, erythropoietin administration, and immune suppression have been proposed as triggering factors in NSF. The proposed mechanisms responsible for fibrosis in NSF have centered on a collagen-producing cell in the peripheral blood termed the circulating fibrocyte. These cells express CD34 and CD45RO antigens and are capable of producing type I collagen.

Circulating fibrocytes traffic to areas of chronic antigenic stimulation promoting wound repair and fibrotic reactions. Some authors have proposed that materials deposited in the skin might serve as targets for circulating fibrocytes.⁸ Circulating fibrocytes also are known to produce inflammatory cytokines including IL-1 and chemokines such as platelet-derived growth factor, transforming growth factor b, and others capable of propagating fibrotic responses. Increased expression of transforming growth factor has been reported in dendritic cells in NSF lesions and Parsons et al⁹ postulated that transglutaminase-2 activation of this protein may be responsible for inciting fibrosis in NSF. Transglutaminases also are known to be directly activated by Gd.^10,11

Transmetalation has been proposed as a possible operative phenomenon responsible for NSF. Several cations including zinc, copper, iron, and carbon are known to compete with Gd and may displace it from the ligand, with anions such as OHe, PO4 3e, and CO3 2e binding the resultant free Gd. Some GBCAs contain excess ligand to diminish potential free Gd concentrations. In fact, substantial elevations of serum calcium and phosphorus in patients with NSF have been noted in a large series of patients with NSF. Calciphylaxis, an often catastrophic condition arising in patients with renal failure, has been described in association with NSF, and sodium thiosulfate has been used with success in treating both conditions.¹⁰ In addition, Sanyal et al¹² noted a substantially higher serum calcium in NSF cases compared with controls.

Gadolinium plays an important role in the pathology of NSF and is confirmed by the presence of Gd in skin biopsies.

To the Editor:

A 68-year-old man with a history of myelodysplastic syndrome and recurrent Sweet syndrome presented with left leg lesions of 3 months’ duration. The lesions originated as a solitary nodule on the left calf and subsequently developed into multiple nonpainful, nonpruritic, erythematous plaques of varying sizes with violaceous coloration and overlying necrotic eschar, occupying the entire anterior aspect of the left lower leg and left popliteal fossa (Figure). The patient denied any trauma or associated symptoms but had a history of Sweet syndrome that manifested as lesions on the arms and legs for which he took 6 mg of prednisone daily to prevent recurrence.

Multiple erythematous to violaceous plaques with overlying necrotic eschar on the anterior aspect of the left lower leg.

Histologic examination revealed nodular and diffuse chronic granulomatous and acute inflammatory infiltrate. Stains for bacteria, fungi, and acid-fast bacilli were negative. Cultures subsequently grew Mycobacterium kansasii, and the patient was started on isoniazid 300 mg daily, rifampin 600 mg daily, ethambutol 800 mg daily, and pyridoxine 50 mg daily. Chest radiograph and computed tomography showed no evidence of pulmonary disease and 2 blood cultures were negative for growth. The patient subsequently developed weakness that he attributed to the antibiotics and he decided to discontinue all treatment.

At 11 months the lesions showed no change; however, magnetic resonance imaging of the leg was suggestive of osteomyelitis. The patient was started on clarithromycin 500 mg twice daily with planned addition of isoniazid. The patient refused any additional antibiotics but agreed to continue the clarithromycin treatment for one year. He was subsequently lost to dermatology follow-up.

Nontuberculous mycobacteria (NTM) infection is a rare sequela of hematologic malignancy, seen in only 1.5% of patients.¹ The NTM most commonly seen in hematologic malignancy are generally the fast-growing species Mycobacterium abscessus, Mycobacterium chelonae, Mycobacterium fortuitum, or Mycobacterium phlei, rather than slow growers Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium kansasii, Mycobacterium marinum, and Mycobacterium xenopi. Mycobacterium kansasii infection, such as seen in our patient, accounts for only 18% of cases.¹ This case is further distinguished by the fact that cutaneous infections with NTM also are generally caused by fast-growing organisms such as Mycobacterium abscessus-chelonae complex and M fortuitum, rather than the slow-growing M kansasii.^2,3

Mycobacterium kansasii is a slow-growing, acid-fast bacillus found in local water reservoirs, swimming pools, sewers, and tap water where it can live for up to 12 months.^2,4,5Mycobacterium kansasii is traditionally considered the most virulent NTM.^3,6 It most frequently causes a pulmonary infection in the immunosuppressed and patients with chronic bronchopulmonary disease.^6,7 Disseminated disease is less common and is primarily seen in immunocompromised patients, particularly in human immunodeficiency virus–positive patients, transplant recipients, and patients with hematologic malignancies.^1,6,8 Disseminated disease rarely has been seen in patients with normal immune function.^2,3

Cutaneous M kansasii infection has only infrequently been described. Most patients tend to be middle-aged men, with a median affected age of 43 years.^2,7,9,10 One review of cutaneous cases found that 72% had some form of altered immunity and more than 50% of those patients were on chronic steroids. The same review found that of the cases of cutaneous M kansasii in patients with altered immunity, only 30% had disseminated disease.¹⁰ Our patient was immunocompromised but showed no evidence of disseminated disease, as displayed by negative chest radiograph and computed tomography, lack of pulmonary symptoms, and negative blood cultures. As a 68-year-old man with myelodysplastic syndrome on chronic steroids with no disseminated disease, our patient fits well into these demographics, aside from his advanced age.

Cutaneous M kansasii infection has a variable presentation, manifesting as solitary lesions, nodules, pustules, seromas, erythematous plaques, verrucous lesions, ulcers, and as cellulitis.^5,7,9-12 Immune competent individuals were more likely to present with raised lesions or ulcers, whereas immune compromised individuals had a more diffuse presentation of cellulitis or seromas with variable histology.^6,8 Our patient, though immune compromised, presented with multiple erythematous plaques with eschars, which further endorses having a high clinical suspicion, as the lesions display marked heterogeneity.

Treatment of M kansasii infection consists of at least 1 year of isoniazid 300 mg daily, rifampin 600 mg daily, and ethambutol 15 mg/kg daily, with possible addition of streptomycin.^8,13Mycobacterium kansasii infection necessitates multidrug treatment due to the broad range of resistance exhibited by different isolated strains.¹⁴

Response to treatment in cutaneous M kansasii greatly depends on the underlying disease state of the individual. Generally, immune competent individuals do very well, while the course in immune compromised patients depends on their degree of illness. Patients with disseminated disease generally do poorly.^4,7,10 In at least one case of cutaneous disease, dissemination developed as a sequela, thus suggesting treatment is needed even in stable lesions.² Dissemination was a concern with our patient given the magnetic resonance imaging findings suggestive of osteomyelitis. Although treatment generally consists of triple therapy with isoniazid, rifampin, and ethambutol, given the high frequency of adverse effects due to isoniazid or rifampin, as was seen in our patient, the drug regimen might have to be altered to suit the patient. Susceptibility testing is desirable to aid in tailoring the treatment.^8,13 Furthermore, as the duration of treatment is at least 1 year, diligent follow-up must be maintained to avoid incomplete treatment.

The unpredictable presentation of cutaneous M kansasii infection coupled with the variable history necessitates a high level of clinical suspicion and a low threshold for culturing lesions. Furthermore, the long duration and complexity of the antibiotic regimen and the high incidence of adverse reactions demands strict follow-up, especially given the risk for progression to disseminated disease.

To the Editor:

A 68-year-old man with a history of myelodysplastic syndrome and recurrent Sweet syndrome presented with left leg lesions of 3 months’ duration. The lesions originated as a solitary nodule on the left calf and subsequently developed into multiple nonpainful, nonpruritic, erythematous plaques of varying sizes with violaceous coloration and overlying necrotic eschar, occupying the entire anterior aspect of the left lower leg and left popliteal fossa (Figure). The patient denied any trauma or associated symptoms but had a history of Sweet syndrome that manifested as lesions on the arms and legs for which he took 6 mg of prednisone daily to prevent recurrence.

Multiple erythematous to violaceous plaques with overlying necrotic eschar on the anterior aspect of the left lower leg.

Histologic examination revealed nodular and diffuse chronic granulomatous and acute inflammatory infiltrate. Stains for bacteria, fungi, and acid-fast bacilli were negative. Cultures subsequently grew Mycobacterium kansasii, and the patient was started on isoniazid 300 mg daily, rifampin 600 mg daily, ethambutol 800 mg daily, and pyridoxine 50 mg daily. Chest radiograph and computed tomography showed no evidence of pulmonary disease and 2 blood cultures were negative for growth. The patient subsequently developed weakness that he attributed to the antibiotics and he decided to discontinue all treatment.

At 11 months the lesions showed no change; however, magnetic resonance imaging of the leg was suggestive of osteomyelitis. The patient was started on clarithromycin 500 mg twice daily with planned addition of isoniazid. The patient refused any additional antibiotics but agreed to continue the clarithromycin treatment for one year. He was subsequently lost to dermatology follow-up.

Nontuberculous mycobacteria (NTM) infection is a rare sequela of hematologic malignancy, seen in only 1.5% of patients.¹ The NTM most commonly seen in hematologic malignancy are generally the fast-growing species Mycobacterium abscessus, Mycobacterium chelonae, Mycobacterium fortuitum, or Mycobacterium phlei, rather than slow growers Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium kansasii, Mycobacterium marinum, and Mycobacterium xenopi. Mycobacterium kansasii infection, such as seen in our patient, accounts for only 18% of cases.¹ This case is further distinguished by the fact that cutaneous infections with NTM also are generally caused by fast-growing organisms such as Mycobacterium abscessus-chelonae complex and M fortuitum, rather than the slow-growing M kansasii.^2,3

Mycobacterium kansasii is a slow-growing, acid-fast bacillus found in local water reservoirs, swimming pools, sewers, and tap water where it can live for up to 12 months.^2,4,5Mycobacterium kansasii is traditionally considered the most virulent NTM.^3,6 It most frequently causes a pulmonary infection in the immunosuppressed and patients with chronic bronchopulmonary disease.^6,7 Disseminated disease is less common and is primarily seen in immunocompromised patients, particularly in human immunodeficiency virus–positive patients, transplant recipients, and patients with hematologic malignancies.^1,6,8 Disseminated disease rarely has been seen in patients with normal immune function.^2,3

Cutaneous M kansasii infection has only infrequently been described. Most patients tend to be middle-aged men, with a median affected age of 43 years.^2,7,9,10 One review of cutaneous cases found that 72% had some form of altered immunity and more than 50% of those patients were on chronic steroids. The same review found that of the cases of cutaneous M kansasii in patients with altered immunity, only 30% had disseminated disease.¹⁰ Our patient was immunocompromised but showed no evidence of disseminated disease, as displayed by negative chest radiograph and computed tomography, lack of pulmonary symptoms, and negative blood cultures. As a 68-year-old man with myelodysplastic syndrome on chronic steroids with no disseminated disease, our patient fits well into these demographics, aside from his advanced age.

Cutaneous M kansasii infection has a variable presentation, manifesting as solitary lesions, nodules, pustules, seromas, erythematous plaques, verrucous lesions, ulcers, and as cellulitis.^5,7,9-12 Immune competent individuals were more likely to present with raised lesions or ulcers, whereas immune compromised individuals had a more diffuse presentation of cellulitis or seromas with variable histology.^6,8 Our patient, though immune compromised, presented with multiple erythematous plaques with eschars, which further endorses having a high clinical suspicion, as the lesions display marked heterogeneity.

Treatment of M kansasii infection consists of at least 1 year of isoniazid 300 mg daily, rifampin 600 mg daily, and ethambutol 15 mg/kg daily, with possible addition of streptomycin.^8,13Mycobacterium kansasii infection necessitates multidrug treatment due to the broad range of resistance exhibited by different isolated strains.¹⁴

Response to treatment in cutaneous M kansasii greatly depends on the underlying disease state of the individual. Generally, immune competent individuals do very well, while the course in immune compromised patients depends on their degree of illness. Patients with disseminated disease generally do poorly.^4,7,10 In at least one case of cutaneous disease, dissemination developed as a sequela, thus suggesting treatment is needed even in stable lesions.² Dissemination was a concern with our patient given the magnetic resonance imaging findings suggestive of osteomyelitis. Although treatment generally consists of triple therapy with isoniazid, rifampin, and ethambutol, given the high frequency of adverse effects due to isoniazid or rifampin, as was seen in our patient, the drug regimen might have to be altered to suit the patient. Susceptibility testing is desirable to aid in tailoring the treatment.^8,13 Furthermore, as the duration of treatment is at least 1 year, diligent follow-up must be maintained to avoid incomplete treatment.

The unpredictable presentation of cutaneous M kansasii infection coupled with the variable history necessitates a high level of clinical suspicion and a low threshold for culturing lesions. Furthermore, the long duration and complexity of the antibiotic regimen and the high incidence of adverse reactions demands strict follow-up, especially given the risk for progression to disseminated disease.

To the Editor:

A 68-year-old man with a history of myelodysplastic syndrome and recurrent Sweet syndrome presented with left leg lesions of 3 months’ duration. The lesions originated as a solitary nodule on the left calf and subsequently developed into multiple nonpainful, nonpruritic, erythematous plaques of varying sizes with violaceous coloration and overlying necrotic eschar, occupying the entire anterior aspect of the left lower leg and left popliteal fossa (Figure). The patient denied any trauma or associated symptoms but had a history of Sweet syndrome that manifested as lesions on the arms and legs for which he took 6 mg of prednisone daily to prevent recurrence.

Multiple erythematous to violaceous plaques with overlying necrotic eschar on the anterior aspect of the left lower leg.

Histologic examination revealed nodular and diffuse chronic granulomatous and acute inflammatory infiltrate. Stains for bacteria, fungi, and acid-fast bacilli were negative. Cultures subsequently grew Mycobacterium kansasii, and the patient was started on isoniazid 300 mg daily, rifampin 600 mg daily, ethambutol 800 mg daily, and pyridoxine 50 mg daily. Chest radiograph and computed tomography showed no evidence of pulmonary disease and 2 blood cultures were negative for growth. The patient subsequently developed weakness that he attributed to the antibiotics and he decided to discontinue all treatment.

At 11 months the lesions showed no change; however, magnetic resonance imaging of the leg was suggestive of osteomyelitis. The patient was started on clarithromycin 500 mg twice daily with planned addition of isoniazid. The patient refused any additional antibiotics but agreed to continue the clarithromycin treatment for one year. He was subsequently lost to dermatology follow-up.

Nontuberculous mycobacteria (NTM) infection is a rare sequela of hematologic malignancy, seen in only 1.5% of patients.¹ The NTM most commonly seen in hematologic malignancy are generally the fast-growing species Mycobacterium abscessus, Mycobacterium chelonae, Mycobacterium fortuitum, or Mycobacterium phlei, rather than slow growers Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium kansasii, Mycobacterium marinum, and Mycobacterium xenopi. Mycobacterium kansasii infection, such as seen in our patient, accounts for only 18% of cases.¹ This case is further distinguished by the fact that cutaneous infections with NTM also are generally caused by fast-growing organisms such as Mycobacterium abscessus-chelonae complex and M fortuitum, rather than the slow-growing M kansasii.^2,3

Mycobacterium kansasii is a slow-growing, acid-fast bacillus found in local water reservoirs, swimming pools, sewers, and tap water where it can live for up to 12 months.^2,4,5Mycobacterium kansasii is traditionally considered the most virulent NTM.^3,6 It most frequently causes a pulmonary infection in the immunosuppressed and patients with chronic bronchopulmonary disease.^6,7 Disseminated disease is less common and is primarily seen in immunocompromised patients, particularly in human immunodeficiency virus–positive patients, transplant recipients, and patients with hematologic malignancies.^1,6,8 Disseminated disease rarely has been seen in patients with normal immune function.^2,3

Cutaneous M kansasii infection has only infrequently been described. Most patients tend to be middle-aged men, with a median affected age of 43 years.^2,7,9,10 One review of cutaneous cases found that 72% had some form of altered immunity and more than 50% of those patients were on chronic steroids. The same review found that of the cases of cutaneous M kansasii in patients with altered immunity, only 30% had disseminated disease.¹⁰ Our patient was immunocompromised but showed no evidence of disseminated disease, as displayed by negative chest radiograph and computed tomography, lack of pulmonary symptoms, and negative blood cultures. As a 68-year-old man with myelodysplastic syndrome on chronic steroids with no disseminated disease, our patient fits well into these demographics, aside from his advanced age.

Cutaneous M kansasii infection has a variable presentation, manifesting as solitary lesions, nodules, pustules, seromas, erythematous plaques, verrucous lesions, ulcers, and as cellulitis.^5,7,9-12 Immune competent individuals were more likely to present with raised lesions or ulcers, whereas immune compromised individuals had a more diffuse presentation of cellulitis or seromas with variable histology.^6,8 Our patient, though immune compromised, presented with multiple erythematous plaques with eschars, which further endorses having a high clinical suspicion, as the lesions display marked heterogeneity.

Treatment of M kansasii infection consists of at least 1 year of isoniazid 300 mg daily, rifampin 600 mg daily, and ethambutol 15 mg/kg daily, with possible addition of streptomycin.^8,13Mycobacterium kansasii infection necessitates multidrug treatment due to the broad range of resistance exhibited by different isolated strains.¹⁴

Response to treatment in cutaneous M kansasii greatly depends on the underlying disease state of the individual. Generally, immune competent individuals do very well, while the course in immune compromised patients depends on their degree of illness. Patients with disseminated disease generally do poorly.^4,7,10 In at least one case of cutaneous disease, dissemination developed as a sequela, thus suggesting treatment is needed even in stable lesions.² Dissemination was a concern with our patient given the magnetic resonance imaging findings suggestive of osteomyelitis. Although treatment generally consists of triple therapy with isoniazid, rifampin, and ethambutol, given the high frequency of adverse effects due to isoniazid or rifampin, as was seen in our patient, the drug regimen might have to be altered to suit the patient. Susceptibility testing is desirable to aid in tailoring the treatment.^8,13 Furthermore, as the duration of treatment is at least 1 year, diligent follow-up must be maintained to avoid incomplete treatment.

The unpredictable presentation of cutaneous M kansasii infection coupled with the variable history necessitates a high level of clinical suspicion and a low threshold for culturing lesions. Furthermore, the long duration and complexity of the antibiotic regimen and the high incidence of adverse reactions demands strict follow-up, especially given the risk for progression to disseminated disease.