Diya F. Mutasim, MD

To the Editor:

Pemphigus vulgaris (PV) is an acquired autoimmune bullous disease with notable morbidity and mortality if not treated appropriately due to loss of epidermal barrier function and subsequent infection and loss of body fluids. Although the use of systemic corticosteroids and immunosuppressive agents has improved the prognosis, these drugs also may have severe adverse effects, especially in elderly patients. Hence, alternative and safer therapies with anti-inflammatory and immunomodulatory agents such as tetracyclines and nicotinamide have been used with variable results. We report a case of PV that was successfully treated with doxycycline.

An 81-year-old man presented with well-demarcated erosions with overlying yellow crust as well as vesicles and pustules on the scalp (Figure 1A), forehead, bilateral cheeks, and upper back (Figure 1B) of 6 months’ duration. He used topical fluorouracil in the month prior to presentation for suspected actinic keratosis but had stopped its use after 2 weeks. At the first visit, a diagnosis of a reaction to topical fluorouracil with secondary bacterial infection was made and he was prescribed doxycycline hyclate 100 mg twice daily. The patient returned 4 weeks later for follow-up and reported initial notable improvement with subsequent worsening of lesions after he ran out of doxycycline. On physical examination the lesions had considerably improved from the last visit, but he still had a few erosions on the scalp and a few in the oral mucosa. A 1-cm shallow erosion with minimal surrounding erythema on the forehead was present, along with fewer scattered, edematous, erythematous plaques on the back and chest. Pemphigus vulgaris was suspected and 2 shave biopsies from the lesions on the back and cheek were obtained for confirmation. Histopathologic examination revealed epidermal hyperplasia and suprabasal acantholysis as well as moderate perivascular and perifollicular lymphocytic infiltrate with several eosinophils and plasma cells, characteristic of PV (Figure 2). Direct immunofluorescence showed moderate intercellular deposition of IgG within the basal layer and to a lesser extent within suprabasal layers as well as moderate intercellular deposition of C3 within the basal layer, characteristic of PV. IgA and IgM were not present. Indirect immunofluorescence using monkey esophagus revealed no antibodies against the intercellular space of the basement membrane zone. Due to the dramatic response, he continued on doxycycline 100 mg twice daily and remained in complete remission. Ten months after initiating treatment he discontinued doxycycline for 2 days and developed a 1-cm lesion on the left cheek. He resumed treatment with clearing of lesions and was slowly tapered to 50 mg of doxycycline once daily, remaining in complete remission (Figure 3). Doxycycline was discontinued 16 months after initiation; he has remained clear at 13 weeks.

The treatment of PV is challenging given the multiple side effects of steroids, especially in elderly patients. Tetracyclines have an advantageous side-effect profile and they have been shown to be efficacious in treating PV when combined with nicotinamide or when used as adjuvant therapy to steroids.^1-3 Our case shows a patient who was treated exclusively with doxycycline and achieved complete remission.

Tetracyclines have multiple biological activities in addition to their antimicrobial function that may provide a therapeutic benefit in PV. They possess immunomodulatory and anti-inflammatory effects by inhibiting leukocyte chemotaxis and activation^4-8 and inhibiting cytokine release. They inhibit matrix metalloproteinases, which are the major enzymes responsible for breakdown of the extracellular matrix,⁹ and they indirectly inhibit neutrophil elastase by protecting α₁-protease inhibitor from matrix metalloproteinase degradation.¹⁰ Additionally, tetracyclines increase the cohesion of the dermoepidermal junction¹¹; whether they increase the adhesion between epidermal cells is unknown. It has been determined that CD4⁺ T cells play an essential role in the pathogenesis of PV by promoting anti-desmoglein 3 antibody production.¹² Szeto et al¹³ reported that minocycline, a member of the tetracycline family, has suppressive effects on CD4⁺ T-cell activation by hindering the activation of nuclear factor of activated T cells (NFAT), a key regulatory factor in T-cell activation. We hypothesize that doxycycline exerted what appears to be immunomodulatory properties in our patient by suppressing CD4⁺ T-cell activity.

In conclusion, tetracyclines can be an effective and promising therapy for PV given their relatively few side effects and immunomodulating properties. However, further randomized controlled trials will be important to support our conclusion.

To the Editor:

Pemphigus vulgaris (PV) is an acquired autoimmune bullous disease with notable morbidity and mortality if not treated appropriately due to loss of epidermal barrier function and subsequent infection and loss of body fluids. Although the use of systemic corticosteroids and immunosuppressive agents has improved the prognosis, these drugs also may have severe adverse effects, especially in elderly patients. Hence, alternative and safer therapies with anti-inflammatory and immunomodulatory agents such as tetracyclines and nicotinamide have been used with variable results. We report a case of PV that was successfully treated with doxycycline.

An 81-year-old man presented with well-demarcated erosions with overlying yellow crust as well as vesicles and pustules on the scalp (Figure 1A), forehead, bilateral cheeks, and upper back (Figure 1B) of 6 months’ duration. He used topical fluorouracil in the month prior to presentation for suspected actinic keratosis but had stopped its use after 2 weeks. At the first visit, a diagnosis of a reaction to topical fluorouracil with secondary bacterial infection was made and he was prescribed doxycycline hyclate 100 mg twice daily. The patient returned 4 weeks later for follow-up and reported initial notable improvement with subsequent worsening of lesions after he ran out of doxycycline. On physical examination the lesions had considerably improved from the last visit, but he still had a few erosions on the scalp and a few in the oral mucosa. A 1-cm shallow erosion with minimal surrounding erythema on the forehead was present, along with fewer scattered, edematous, erythematous plaques on the back and chest. Pemphigus vulgaris was suspected and 2 shave biopsies from the lesions on the back and cheek were obtained for confirmation. Histopathologic examination revealed epidermal hyperplasia and suprabasal acantholysis as well as moderate perivascular and perifollicular lymphocytic infiltrate with several eosinophils and plasma cells, characteristic of PV (Figure 2). Direct immunofluorescence showed moderate intercellular deposition of IgG within the basal layer and to a lesser extent within suprabasal layers as well as moderate intercellular deposition of C3 within the basal layer, characteristic of PV. IgA and IgM were not present. Indirect immunofluorescence using monkey esophagus revealed no antibodies against the intercellular space of the basement membrane zone. Due to the dramatic response, he continued on doxycycline 100 mg twice daily and remained in complete remission. Ten months after initiating treatment he discontinued doxycycline for 2 days and developed a 1-cm lesion on the left cheek. He resumed treatment with clearing of lesions and was slowly tapered to 50 mg of doxycycline once daily, remaining in complete remission (Figure 3). Doxycycline was discontinued 16 months after initiation; he has remained clear at 13 weeks.

The treatment of PV is challenging given the multiple side effects of steroids, especially in elderly patients. Tetracyclines have an advantageous side-effect profile and they have been shown to be efficacious in treating PV when combined with nicotinamide or when used as adjuvant therapy to steroids.^1-3 Our case shows a patient who was treated exclusively with doxycycline and achieved complete remission.

Tetracyclines have multiple biological activities in addition to their antimicrobial function that may provide a therapeutic benefit in PV. They possess immunomodulatory and anti-inflammatory effects by inhibiting leukocyte chemotaxis and activation^4-8 and inhibiting cytokine release. They inhibit matrix metalloproteinases, which are the major enzymes responsible for breakdown of the extracellular matrix,⁹ and they indirectly inhibit neutrophil elastase by protecting α₁-protease inhibitor from matrix metalloproteinase degradation.¹⁰ Additionally, tetracyclines increase the cohesion of the dermoepidermal junction¹¹; whether they increase the adhesion between epidermal cells is unknown. It has been determined that CD4⁺ T cells play an essential role in the pathogenesis of PV by promoting anti-desmoglein 3 antibody production.¹² Szeto et al¹³ reported that minocycline, a member of the tetracycline family, has suppressive effects on CD4⁺ T-cell activation by hindering the activation of nuclear factor of activated T cells (NFAT), a key regulatory factor in T-cell activation. We hypothesize that doxycycline exerted what appears to be immunomodulatory properties in our patient by suppressing CD4⁺ T-cell activity.

In conclusion, tetracyclines can be an effective and promising therapy for PV given their relatively few side effects and immunomodulating properties. However, further randomized controlled trials will be important to support our conclusion.

To the Editor:

Pemphigus vulgaris (PV) is an acquired autoimmune bullous disease with notable morbidity and mortality if not treated appropriately due to loss of epidermal barrier function and subsequent infection and loss of body fluids. Although the use of systemic corticosteroids and immunosuppressive agents has improved the prognosis, these drugs also may have severe adverse effects, especially in elderly patients. Hence, alternative and safer therapies with anti-inflammatory and immunomodulatory agents such as tetracyclines and nicotinamide have been used with variable results. We report a case of PV that was successfully treated with doxycycline.

An 81-year-old man presented with well-demarcated erosions with overlying yellow crust as well as vesicles and pustules on the scalp (Figure 1A), forehead, bilateral cheeks, and upper back (Figure 1B) of 6 months’ duration. He used topical fluorouracil in the month prior to presentation for suspected actinic keratosis but had stopped its use after 2 weeks. At the first visit, a diagnosis of a reaction to topical fluorouracil with secondary bacterial infection was made and he was prescribed doxycycline hyclate 100 mg twice daily. The patient returned 4 weeks later for follow-up and reported initial notable improvement with subsequent worsening of lesions after he ran out of doxycycline. On physical examination the lesions had considerably improved from the last visit, but he still had a few erosions on the scalp and a few in the oral mucosa. A 1-cm shallow erosion with minimal surrounding erythema on the forehead was present, along with fewer scattered, edematous, erythematous plaques on the back and chest. Pemphigus vulgaris was suspected and 2 shave biopsies from the lesions on the back and cheek were obtained for confirmation. Histopathologic examination revealed epidermal hyperplasia and suprabasal acantholysis as well as moderate perivascular and perifollicular lymphocytic infiltrate with several eosinophils and plasma cells, characteristic of PV (Figure 2). Direct immunofluorescence showed moderate intercellular deposition of IgG within the basal layer and to a lesser extent within suprabasal layers as well as moderate intercellular deposition of C3 within the basal layer, characteristic of PV. IgA and IgM were not present. Indirect immunofluorescence using monkey esophagus revealed no antibodies against the intercellular space of the basement membrane zone. Due to the dramatic response, he continued on doxycycline 100 mg twice daily and remained in complete remission. Ten months after initiating treatment he discontinued doxycycline for 2 days and developed a 1-cm lesion on the left cheek. He resumed treatment with clearing of lesions and was slowly tapered to 50 mg of doxycycline once daily, remaining in complete remission (Figure 3). Doxycycline was discontinued 16 months after initiation; he has remained clear at 13 weeks.

The treatment of PV is challenging given the multiple side effects of steroids, especially in elderly patients. Tetracyclines have an advantageous side-effect profile and they have been shown to be efficacious in treating PV when combined with nicotinamide or when used as adjuvant therapy to steroids.^1-3 Our case shows a patient who was treated exclusively with doxycycline and achieved complete remission.

Tetracyclines have multiple biological activities in addition to their antimicrobial function that may provide a therapeutic benefit in PV. They possess immunomodulatory and anti-inflammatory effects by inhibiting leukocyte chemotaxis and activation^4-8 and inhibiting cytokine release. They inhibit matrix metalloproteinases, which are the major enzymes responsible for breakdown of the extracellular matrix,⁹ and they indirectly inhibit neutrophil elastase by protecting α₁-protease inhibitor from matrix metalloproteinase degradation.¹⁰ Additionally, tetracyclines increase the cohesion of the dermoepidermal junction¹¹; whether they increase the adhesion between epidermal cells is unknown. It has been determined that CD4⁺ T cells play an essential role in the pathogenesis of PV by promoting anti-desmoglein 3 antibody production.¹² Szeto et al¹³ reported that minocycline, a member of the tetracycline family, has suppressive effects on CD4⁺ T-cell activation by hindering the activation of nuclear factor of activated T cells (NFAT), a key regulatory factor in T-cell activation. We hypothesize that doxycycline exerted what appears to be immunomodulatory properties in our patient by suppressing CD4⁺ T-cell activity.

In conclusion, tetracyclines can be an effective and promising therapy for PV given their relatively few side effects and immunomodulating properties. However, further randomized controlled trials will be important to support our conclusion.

The Diagnosis: Tumor of the Follicular Infundibulum

Histopathologic findings from a facial papule in our patient revealed multifocal hyperplasia of anastomosing follicular infundibular cells with multiple connections to the overlying epidermis (Figure). There was no atypia. Gomori methenamine-silver and periodic acid–Schiff stains for fungi were negative. The combined clinical presentation and histopathologic findings supported the diagnosis of multiple tumor of the follicular infundibulum (TFI).

Tumor of the follicular infundibulum was diagnosed based on a biopsy from the right cheek that revealed multifocal hyperplasia of anastomosing follicular infundibular cells with multiple connections to the overlying epidermis (A and B)(H&E, original magnifications ×40 and ×100).

Tumor of the follicular infundibulum is an uncommon benign neoplasm that was first described in 1961 by Mehregan and Butler.¹ The reported frequency is 10 per 100,000 biopsies.² The majority of cases have been reported as solitary lesions, and multiple TFI are rare.³ Tumor of the follicular infundibulum affects middle-aged and elderly individuals with a female predominance.⁴ Multiple lesions generally range in number from 10 to 20, but there are few reports of more than 100 lesions.^2,3,5,6 The solitary tumors often are initially misdiagnosed as basal cell carcinomas (BCCs) or seborrheic keratosis. Multiple TFI have been described variably as hypopigmented, flesh-colored and pink, flat and slightly depressed macules and thin papules. Sites of predilection include the scalp, face, neck, and upper trunk.^2,3,5

There is no histopathologic difference between solitary and multiple TFI. Tumor of the follicular infundibulum displays a characteristic pale platelike proliferation of keratinocytes within the upper dermis attached to the overlying epidermis. The proliferating cells stain positive with periodic acid–Schiff, diastase-digestible glycogen is present in the cells at the base of the tumor, and a thickened network or brushlike pattern of elastic fibers surrounds the periphery of the tumor.¹ Tumor of the follicular infundibulum is occasionally discovered incidentally on biopsy and has been observed in the margin of wide excisions of a variety of neoplasms including BCC.⁷ Based on the close association of TFI and BCC in the same specimens, Weyers et al⁷ concluded that TFI may be a nonaggressive type of BCC. Cribier and Grosshans² reported 2 cases of TFI overlying a nevus sebaceous and a fibroma.

Treatment of TFI includes topical keratolytics, topical retinoic acid,⁵ imiquimod,⁸ topical steroids, and oral etretinate,⁶ all of which result in minimal improvement or incomplete resolution. Destructive treatments include cryotherapy, curettage, electrosurgery, laser ablation, and surgical excision, but all may lead to an unacceptable cosmetic result.

The Diagnosis: Tumor of the Follicular Infundibulum

Histopathologic findings from a facial papule in our patient revealed multifocal hyperplasia of anastomosing follicular infundibular cells with multiple connections to the overlying epidermis (Figure). There was no atypia. Gomori methenamine-silver and periodic acid–Schiff stains for fungi were negative. The combined clinical presentation and histopathologic findings supported the diagnosis of multiple tumor of the follicular infundibulum (TFI).

Tumor of the follicular infundibulum was diagnosed based on a biopsy from the right cheek that revealed multifocal hyperplasia of anastomosing follicular infundibular cells with multiple connections to the overlying epidermis (A and B)(H&E, original magnifications ×40 and ×100).

Tumor of the follicular infundibulum is an uncommon benign neoplasm that was first described in 1961 by Mehregan and Butler.¹ The reported frequency is 10 per 100,000 biopsies.² The majority of cases have been reported as solitary lesions, and multiple TFI are rare.³ Tumor of the follicular infundibulum affects middle-aged and elderly individuals with a female predominance.⁴ Multiple lesions generally range in number from 10 to 20, but there are few reports of more than 100 lesions.^2,3,5,6 The solitary tumors often are initially misdiagnosed as basal cell carcinomas (BCCs) or seborrheic keratosis. Multiple TFI have been described variably as hypopigmented, flesh-colored and pink, flat and slightly depressed macules and thin papules. Sites of predilection include the scalp, face, neck, and upper trunk.^2,3,5

There is no histopathologic difference between solitary and multiple TFI. Tumor of the follicular infundibulum displays a characteristic pale platelike proliferation of keratinocytes within the upper dermis attached to the overlying epidermis. The proliferating cells stain positive with periodic acid–Schiff, diastase-digestible glycogen is present in the cells at the base of the tumor, and a thickened network or brushlike pattern of elastic fibers surrounds the periphery of the tumor.¹ Tumor of the follicular infundibulum is occasionally discovered incidentally on biopsy and has been observed in the margin of wide excisions of a variety of neoplasms including BCC.⁷ Based on the close association of TFI and BCC in the same specimens, Weyers et al⁷ concluded that TFI may be a nonaggressive type of BCC. Cribier and Grosshans² reported 2 cases of TFI overlying a nevus sebaceous and a fibroma.

Treatment of TFI includes topical keratolytics, topical retinoic acid,⁵ imiquimod,⁸ topical steroids, and oral etretinate,⁶ all of which result in minimal improvement or incomplete resolution. Destructive treatments include cryotherapy, curettage, electrosurgery, laser ablation, and surgical excision, but all may lead to an unacceptable cosmetic result.

The Diagnosis: Tumor of the Follicular Infundibulum

Histopathologic findings from a facial papule in our patient revealed multifocal hyperplasia of anastomosing follicular infundibular cells with multiple connections to the overlying epidermis (Figure). There was no atypia. Gomori methenamine-silver and periodic acid–Schiff stains for fungi were negative. The combined clinical presentation and histopathologic findings supported the diagnosis of multiple tumor of the follicular infundibulum (TFI).

Tumor of the follicular infundibulum was diagnosed based on a biopsy from the right cheek that revealed multifocal hyperplasia of anastomosing follicular infundibular cells with multiple connections to the overlying epidermis (A and B)(H&E, original magnifications ×40 and ×100).

Tumor of the follicular infundibulum is an uncommon benign neoplasm that was first described in 1961 by Mehregan and Butler.¹ The reported frequency is 10 per 100,000 biopsies.² The majority of cases have been reported as solitary lesions, and multiple TFI are rare.³ Tumor of the follicular infundibulum affects middle-aged and elderly individuals with a female predominance.⁴ Multiple lesions generally range in number from 10 to 20, but there are few reports of more than 100 lesions.^2,3,5,6 The solitary tumors often are initially misdiagnosed as basal cell carcinomas (BCCs) or seborrheic keratosis. Multiple TFI have been described variably as hypopigmented, flesh-colored and pink, flat and slightly depressed macules and thin papules. Sites of predilection include the scalp, face, neck, and upper trunk.^2,3,5

There is no histopathologic difference between solitary and multiple TFI. Tumor of the follicular infundibulum displays a characteristic pale platelike proliferation of keratinocytes within the upper dermis attached to the overlying epidermis. The proliferating cells stain positive with periodic acid–Schiff, diastase-digestible glycogen is present in the cells at the base of the tumor, and a thickened network or brushlike pattern of elastic fibers surrounds the periphery of the tumor.¹ Tumor of the follicular infundibulum is occasionally discovered incidentally on biopsy and has been observed in the margin of wide excisions of a variety of neoplasms including BCC.⁷ Based on the close association of TFI and BCC in the same specimens, Weyers et al⁷ concluded that TFI may be a nonaggressive type of BCC. Cribier and Grosshans² reported 2 cases of TFI overlying a nevus sebaceous and a fibroma.

Treatment of TFI includes topical keratolytics, topical retinoic acid,⁵ imiquimod,⁸ topical steroids, and oral etretinate,⁶ all of which result in minimal improvement or incomplete resolution. Destructive treatments include cryotherapy, curettage, electrosurgery, laser ablation, and surgical excision, but all may lead to an unacceptable cosmetic result.