Report

Pemphigus herpetiformis: a case series and review of the literature Philip M. Laws, MBCHB, Kara Heelan, MBBCH, Faisal Al-Mohammedi, MD, Scott Walsh, MD, PhD, and Neil H. Shear, MD

Department of Medicine, University of Toronto, Toronto, Ontario, Canada Correspondence Philip M. Laws, MBCHB Division of Dermatology Bayview Campus 2075 Bayview Avenue Toronto, ON Canada M4N 3M5 E-mail: [email protected]

Abstract Background Pemphigus herpetiformis (PH) is a rare subtype of pemphigus that presents challenges in diagnosis. Objective To review the presentation, diagnosis, and management of PH. Methods We reviewed the charts of all patients diagnosed and treated for PH in an immunobullous referral center between September 2007 and June 2013. Results Eight patients were identified with a diagnosis of PH. All presented initially with pruritus. Clinical disease was manifest as either urticated erythematous plaques or a vesiculobullous eruption. Histological evaluation demonstrated eosinophilic spongiosis in all patients with acantholysis in half of cases (n = 4/8). Peripheral eosinophilia was noted in

Conflicts of interest: None.

three of eight (37.5%) patients. In all cases, direct immunofluorescence showed intercellular deposition of immunoglobulin G in the epidermis. All patients required high-dose

doi: 10.1111/ijd.12582

corticosteroid initially. All patients treated with dapsone or sulfasalazine (n = 4) achieved at least partial control. Other effective treatments included intravenous immunoglobulin (n = 2), azathioprine (n = 2), and leflunomide (n = 1). Rituximab was ineffective in two patients. Conclusion The clinical and histological features of PH develop over time and with treatment, making distinction between pemphigus subtypes challenging and delay in diagnosis common. Diagnosis of PH requires a high index of suspicion and is made on clinical grounds (urticated erythema) in the context of compatible histology and immunofluorescence findings. Treatment may be challenging, although efficacy of sulfonamide derivatives appears to offer a therapeutic effect.

Introduction Pemphigus herpetiformis (PH) was originally described by Jablonska et al.1 in 1975, although it had been reported under a variety of different terms, including dermatitis herpetiformis with acantholysis, mixed bullous disease, and sulfonamide-responsive pemphigus. Diagnosis is based on clinical, histological, and direct immunofluorescence (DIF) findings and typically has been regarded as a subtype of pemphigus foliaceus (PF).2 Following the description of a single case, Jablonska et al.1 suggested the diagnosis of PH in patients with a clinical appearance compatible with dermatitis herpetiformis and DIF findings suggestive of pemphigus. To date there are three case series describing PH, two of which are from geographic areas where PF is endemic and may not reflect the typical presentation.3,4 Eight patients who present with PH in a non-endemic area are reported. The clinical, histological, and immunofluorescence findings and subsequent management are ª 2015 The International Society of Dermatology

described. This study clarifies the clinical presentation of this rare disease and its relationship to other forms of pemphigus. Methods A retrospective chart review of patients with a confirmed diagnosis of PH from a large tertiary care dermatology center providing services to the Greater Toronto Area and the province of Ontario (non-endemic area for pemphigus) between September 2007 and June 2013 were analyzed. Diagnostic criteria proposed by Jablonska et al. were eosinophilic spongiosis, epidermal intercellular deposits of immunoglobulin G (IgG), and variable acantholysis.

Case reports Case 1

A 49-year-old man presented with a 3-week history of an intensely pruritic eruption affecting the trunk. There was International Journal of Dermatology 2015

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Figure 1 Clinical appearance of case 1 with arcuate, urticated, and circinate plaques over the trunk, arms, and legs

no mucosal involvement. Clinical examination revealed a vesiculobullous eruption with arcuate, urticated, and circinate plaques over the trunk and limbs (Fig. 1). Blood analysis revealed an eosinophilia of 2.0 9 109 cells/l (0.04–0.44 9 109 cells/l). Skin biopsy demonstrated eosinophilic spongiosis. DIF revealed epidermal IgG in an intercellular pattern. Indirect immunofluorescence (IIF) to pemphigus antibodies using monkey esophagus was positive with a titer of 1 : 160. IIF of rat bladder epithelium was negative. The patient responded well to prednisone 50 mg daily, but disease flared on tapering the dose below 30 mg. Subsequent treatment with azathioprine was not tolerated. Both mycophenolate mofetil (MMF) and dapsone proved ineffective. Owing to evolving disease (consisting of annular erythema with scale and treatment resistance), a repeat biopsy was performed demonstrating eosinophilic spongiosis. Intercellular epidermal IgG was again seen on DIF. IgA was weakly positive in a linear distribution at the basement membrane zone. IIF demonstrated pemphigus antibodies positive at a titer of 1 : 320 ratio. Additional treatment with intravenous immunoglobulin (IVIG, 2 g/kg for 4 weeks) and colchicine was minimally effective. The patient was treated with IVIG and a single cycle of rituximab (1 g on days 1 and 15).5 Despite initial improvement, symptoms rapidly recurred eight weeks later at which point cyclophosphamide 100 mg daily was added. The patient responded well with remission of the PH but relapsed six months later. Addition of sulfasalazine 3 g daily resulted in a marked clinical response such that it was possible to wean both cyclophosphamide and prednisone. He has remained in remission over the last two years on sulfasalazine and IVIG (1 g/kg for 4 weeks). International Journal of Dermatology 2015

Figure 2 Clinical appearance of case 2 with widespread urticated erythema and erosions on the trunk and limbs

Case 2

A 52-year-old woman presented with a 12-month history of an intensely pruritic blistering rash on the trunk and limbs. This had been treated by her general practitioner with prednisone. Past medical history included a remote resected fibrosarcoma and hypertension. Clinical examination revealed erythematous urticated plaques over the trunk and to a lesser extent the limbs (Figs. 2 and 3). There was no mucosal disease.

Figure 3 Clinical appearance of case 2 with widespread urticated erythema and erosions on the trunk and limbs ª 2015 The International Society of Dermatology

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Report

Skin biopsy demonstrated eosinophilic and neutrophilic spongiosis. DIF demonstrated epidermal intercellular IgG and C3 deposition. IIF for pemphigus antibodies was positive with a titer of 1 : 320. The peripheral eosinophil count was normal. The patient was treated with prednisone 50 mg daily to good effect. On tapering the dose, the disease flared and dapsone was added. The patient has remained in remission for two years with dapsone 100 mg daily monotherapy. Case 3

A 65-year-old man presented with a 6-month history of a pruritic eruption on the trunk and limbs. Past medical history included hypertension and type 2 diabetes. Clinical examination revealed annular, urticarial red–brown plaques on the trunk and limbs (Fig. 4). There was no mucosal involvement. Blood analysis revealed an eosinophilia of 1.3 9 109 cells/l (0.04–0.44 9 109 cells/l). Skin biopsies demonstrated eosinophilic spongiosis with a dermal perivascular and interstitial infiltrate of lymphocytes and eosinophils. The DIF initially demonstrated intercellular IgG and C3. A second biopsy demonstrated IgG and C3 with weak IgA in an intercellular pattern. IIF with rat bladder epithelium as substrate was negative. The patient had been initially diagnosed (before immunofluorescence studies), as bullous pemphigoid (BP) and treated with prednisone, tetracycline, and niacinamide. The rash persisted despite prednisone 30 mg daily. Treatment with mycophenolic acid was ineffective, and subsequently azathioprine was only partially effective. Dual therapy with azathioprine 150 mg daily and dapsone 100 mg daily has provided remission over the last two years.

Figure 5 Clinical appearance of case 5 with widespread urticated erythema

Case 4

A 67-year-old woman presented with a 3-month history of a pruritic rash affecting the chest and back. Past medical history included Bell’s palsy and cerebral aneurysm (incidental finding). Clinical examination revealed widespread urticated erythematous plaques with minimal scale (Fig. 5). There was no oral involvement. A biopsy demonstrated epidermal neutrophilic and eosinophilic spongiosis, focal areas of suprabasal acantholysis, and small subcorneal pustules. DIF demonstrated IgG in an intercellular pattern. The peripheral eosinophil count was normal. IIF for pemphigus antibodies was negative. The patient was treated initially with prednisone 50 mg daily. Other treatments included azathioprine (not tolerated), mycophenolic acid (ineffective and prohibitively expensive), sulfasalazine (not tolerated), and subsequently leflunomide. The patient has remained in remission with leflunomide 15 mg daily and prednisone 5 mg daily for 12 months. Case 5

Figure 4 Clinical appearance of case 3 with annular, urticarial red–brown plaques on the trunk and limbs ª 2015 The International Society of Dermatology

A 50-year-old man presented with a 4-week history of a blistering, pruritic rash affecting the trunk and groin. He was otherwise well and not on regular medication. Clinical examination revealed urticated erythema with erosions and crusting affecting much of the trunk and groin. There was no mucosal involvement. Skin biopsies demonstrated focal suprabasal acantholysis with eosinophilic and neutrophilic spongiosis (Figs. 6 and 7). DIF was positive with epidermal IgG and C3 in an intercellular pattern. IIF for pemphigus antibodies was positive with a titer of 1 : 1280. The peripheral eosinophil count was normal. International Journal of Dermatology 2015

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Figure 6 Skin biopsy (9100, hematoxylin and eosin)

demonstrating eosinophilic and neutrophilic spongiosis with focal suprabasal acantholysis

Figure 7 Skin biopsy (9200, hematoxylin and eosin)

demonstrating eosinophilic and neutrophilic spongiosis with focal suprabasal acantholysis

High-dose prednisone (120 mg daily) was required to achieve disease control. The patient was treated with mycophenolic acid 1080 mg twice daily and prednisone tapered to 35 mg daily. Despite the above regimen, the patient continued to experience disease flares and was treated with azathioprine (not tolerated) and subsequently IVIG (1 g/kg for 4 weeks). The disease has remained in remission for four months with low-dose prednisone and monthly IVIG. Case 6

A 34-year-old woman presented with a 3-month history of an intensely itchy rash on the scalp and trunk. She was otherwise well and not on regular medication. Clinical International Journal of Dermatology 2015

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Figure 8 Skin biopsy (9100, hematoxylin and eosin) demonstrating suprabasal acantholysis

Figure 9 Skin biopsy (9200, hematoxylin and eosin) demonstrating suprabasal acantholysis

examination revealed urticated plaques on the trunk and abdomen with superficial erosions on the scalp. There was no oral involvement. Skin biopsies demonstrated suprabasal acantholysis, eosinophilic spongiosis, and a perivascular lymphocytic infiltrate (Figs. 8 and 9). DIF was positive with epidermal IgG and C3 in an intercellular distribution. IIF for pemphigus was reported at 1 : 16. The peripheral eosinophil count was normal. The patient was treated with a tapering course of prednisone 60 mg daily and subsequently azathioprine at 150 mg daily (2 mg/kg). The disease remained under excellent control with azathioprine and low-dose prednisone over 12 months. Following this, the prednisone and azathioprine were withdrawn, and the patient remained ª 2015 The International Society of Dermatology

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Figure 10 Clinical appearance of case 6 with urticated erythema on the trunk

in remission for a further 12 months. The patient then represented with an urticated erythema on the trunk (Fig. 10). There was no mucosal involvement. Skin biopsies demonstrated an eosinophilic spongiosis with no acantholysis. DIF was positive with epidermal IgG and C3 in an intercellular pattern. The patient has been restarted on azathioprine 150 mg daily and a tapering course of prednisone.

Figure 11 Clinical appearance of case 7 with widespread

crusted erythematous plaques

Case 7

A 58-year-old man presented with a 4-month history of widespread rash and intense itch. The patient was known to have pemphigus vulgaris (PV) diagnosed six years previously. He had been treated effectively with methotrexate and prednisone, which had been tapered and discontinued six months previously. Examination revealed widespread, crusted, erythematous plaques (Figs. 11 and 12). There was no mucosal involvement. The patient subjectively reported a different pattern of disease from initial presentation. Skin biopsy demonstrated eosinophilic spongiosis with no acantholysis. DIF revealed epidermal intercellular IgG and C3. IIF was not available for this episode; at initial diagnosis, IgG to desmoglein (Dsg) 1 and 3 were detected. The patient was treated with methotrexate and prednisone with minimal response. Owing to lack of effect, this was stopped and rituximab initiated (1 g on days 1 and 15). Minimal change in disease activity was noted, and the patient was treated with dapsone 100 mg daily to good effect. Case 8

A 52-year-old woman was referred with a long history (>10 years) of PV previously well controlled with prednisone 5–10 mg and MMF 1.5 g twice daily. Background ª 2015 The International Society of Dermatology

Figure 12 Clinical appearance of case 7 with widespread

crusted erythematous plaques

history included type 2 diabetes and osteoporosis (secondary to corticosteroid therapy). The patient had experienced a disease flare of several months duration characterized by widespread urticarial plaques and severe pruritus. Skin biopsy revealed intraepidermal vesicles and eosinophilic and neutrophilic spongiosis with a few acantholytic cells within the granular layer. DIF demonstrated intercellular IgG. IIF was negative. Given the disease flare, despite treatment with prednisone and MMF, the patient was treated with rituximab. Response to rituximab therapy has not yet been determined. International Journal of Dermatology 2015

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Table 1 Clinical, histological and immunofluorescence findings for patients with pemphigus herpetiformis Gender

Age

Clinical pattern

Histology

IIF

DIFa

Case 1

M

49

Eosinophilic spongiosis

1 : 160b

Case 2

F

52

Eosinophilic and neutrophilic spongiosis

1 : 320

IgG IgA BMZ IgG and C3

Case 3

M

65

Urticated erythema Vesiculobullous Urticated erythema Vesiculobullous (pustular) Urticated erythema

Eosinophilic spongiosis

Negative

Case 4

F

67

Urticated erythema

Case 5

M

50

Case 6

F

34

Case 7 Case 8

M F

58 52

Urticated erythema Vesiculobullous Urticated erythema Vesiculobullous Urticated erythema Urticated erythema

Eosinophilic and neutrophilic Suprabasal acantholysis Eosinophilic and neutrophilic Suprabasal acantholysis Eosinophilic and neutrophilic Suprabasal acantholysis Eosinophilic spongiosis Intraepidermal vesicles Eosinophilic and neutrophilic Acantholysis

spongiosis

Negative

IgG and C3 Weak IgA IgG

spongiosis

1 : 1280

IgG and C3

spongiosis

1 : 16

IgG and C3

– Negative

IgG and C3 IgG

spongiosis

BMZ, basement membrane zone; C3, complement component 3; DIF, direct immunofluorescence; IIF, indirect immunofluorescence (to pemphigus antibodies unless otherwise specified); IgG, immunoglobulin G; IgA, immunoglobulin A. a Interepidermal immunofluorescence (unless otherwise specified). b Monkey esophagus. Case summaries

Eight patients are presented with varied ancestry (Asian = 1, Caucasian = 5, Greek = 1, Sri Lankan = 1). Clinical, histological, and immunofluorescence findings are summarized in Table 1. All patients presented with pruritus and an urticated erythema or vesiculobullous eruption. The average age was 53.4 years with no apparent gender predilection. Eosinophilia was noted in 37.5% (n = 3/8). At least partial responsiveness to sulfonamide therapy was observed in all exposed patients (n = 4/4); one patient was intolerant (case 4), and three patients were not treated with a sulfonamide (cases 5, 6, and 8). Two patients achieved a good response with dapsone monotherapy (cases 2 and 7). One patient received leflunomide, achieving remission in combination with low-dose prednisone. Rituximab was minimally effective in disease control for cases 1 and 7. The response to treatment for case 8 remains to be determined. Discussion PH is a rare subtype representing about 7% of pemphigus disease.6 PH in non-endemic areas may occur at any age but most commonly presents in the fifth or sixth decade of life. There is a single report of PH in childhood.7 Three case series of PH are previously described in the literature. Maciejowska et al.6 describe 15 patients with PH in a Polish cohort with an average age of 60.1 years and no gender predilection. In at least two patients, the diagnosis was initially PF and later modified to PH International Journal of Dermatology 2015

following evolution of the disease. In contrast to our study, and previous case reports, only one-third of these patients (five of 15) complained of pruritus. Additionally four of 15 patients had occasional involvement of the oral mucosa. Histology was available for seven of 15 patients. These demonstrated subcutaneous bullae (n = 5/7), neutrophilic microabscesses (n = 3/7), and eosinophilic spongiosis (n = 2/7). Acantholysis was seen in only one patient and reported as mild. DIF invariably demonstrated intercellular IgG and to a lesser extent complement (n = 10/ 12). In one patient, intercellular IgA was positive. A second case series by Santi et al. describes seven patients with PH in Brazil, where fogo selvagem is endemic, with an average age of 54.7 years and no gender predilection.3 This includes four patients initially diagnosed as PF and one diagnosed as PV that later evolved during treatment into PH. Only two patients presented with a clinical picture compatible with PH. Histology at the time of diagnosis of PH demonstrated eosinophilic spongiosis (n = 7/7) and acantholysis (n = 2/7). All patients demonstrated intercellular IgG on DIF and IIF to Dsg1. Antibodies to Dsg1 are typically described in association with PF but are known to overlap with other variants of pemphigus.8 A third case series by Morini et al. describes a Tunisian cohort of seven patients with PH in an area of endemic PF.4 None of this cohort was reported to have oral involvement. This cohort is quite distinct from our cohort and those previously reported in that the average age at presentation was 28 years and all patients were female. Two of the seven patients later progressed to classical PF. ª 2015 The International Society of Dermatology

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Histological evaluation demonstrated eosinophilic spongiosis in all patients with PH, and DIF demonstrated epidermal intercellular IgG. Our findings are consistent with previously reported case series and provide a clearer description of the presentation of PH. The disease typically presents with marked pruritus ( 100%), urticated erythema ( 100%), and/or vesiculobullous lesions ( 50%). Oral involvement is infrequent. Peripheral eosinophilia ( 40%) may occur. An eosinophilia has been reported in four case reports of PH previously but was not described in any of the case series detailed above.1,7,9,10 Histological evaluation demonstrates eosinophilic spongiosis ( 100%), neutrophilic spongiosis ( 50%), and acantholysis (50%). Acantholysis may be subcorneal or suprabasal.11 A diagnosis of PH remains challenging. The differential diagnosis of eosinophilic spongiosis is broad and includes PV, PF, PH, BP, dermatitis, linear IgA bullous Table 2 Diagnostic markers for pemphigus herpetiformis Pruritus Urticated erythema (blister or erosion) Eosinophilic spongiosis Epidermal intercellular deposits of IgG Variable acantholysis

These criteria are not exclusive to pemphigus herpetiformis and should be interpreted in light of the clinical scenario.

Report

dermatosis, drug-induced rashes, and allergic contact dermatitis. In the presence of epidermal intercellular IgG, the diagnosis is narrowed to pemphigus variants. Our cohort provides evidence that PH is diagnosed on clinical grounds in the context of compatible histological and immunofluorescence findings. The diagnostic criteria proposed by Jablonska et al. provide a useful but limited clinical basis on which to distinguish PH from PF or PV. We propose the addition of pruritus and urticated erythema, with variable blistering and/or erosion, to the diagnostic criteria of PH (Table 2). We further support that PH may pre-date or develop subsequent to PF, or less frequently PV. Desmosomal proteins (predominantly Dsg-1 and -3) are the target for pemphigus diseases. An immunoblot assay by Ishii et al. of serum from patients with PH (n = 20) demonstrated reactivity to Dsg-1 (n = 16/20) and Dsg-3 (n = 4/20) but not both.12 This provides further evidence of the overlap of PH with PF and PV. The variable acantholysis discussed above (suprabasal in our cohort compared with predominantly subcorneal in other studies) may relate to different expression of Dsg autoantibodies. Dsg-1 autoantibodies favor subcorneal acantholysis whilst Dsg-3 autoantibodies favor suprabasal acantholysis. The variable presence of acantholysis in PH is poorly understood. One theory may relate to a relative reduction in pathogenicity of autoantibodies in PH when compared to PV or PF. It has previously been demonstrated that the

Table 3 Summary of clinical, histological and immunofluorescence findings in pemphigus subtypes and bullous pemphigoid. Bullous pemphigoid may overlap clinically and histologically, distinction is made on demonstration of epidermal intercellular IgG Pemphigus herpetiformis1 Symptoms Itch +++ Pain + Clinical Mucosae – Urticated erythema +++ Erosions + Blisters + Histology Eosinophils +++ Neutrophils ++ Acantholysis Suprabasal + Subcorneal + Epidermal intercellular immunofluorescence IgG +++ IgA + C3 ++

Pemphigus vulgaris2

Pemphigus foliaceus2

Bullous pemphigoid2

+++

+ +++

+++ +

+++ +/ ++ ++

+ + +

+++ +/ +++

+ +/

++ +

+++ +

+++ +++ +++

+++

++

++

+/–, Observed (but not frequent); +, compatible; ++, common; +++, characteristic. +++ Denotes features distinguishing pemphigus herpetiformis from pemphigus vulgaris and pemphigus foliaceus. ª 2015 The International Society of Dermatology

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dominant epitope for both PF and PV are located on the amino-terminus of Dsg protein, and the ability to induce acantholysis is limited to specific areas of the extracellular domain.13,14 DIF may demonstrate intercellular IgG ( 100%) and C3 ( 65%). Intercellular IgA ( 17%) may also be observed. The variable prevalence of C3 may relate to the IgG subclass. In the case series reported by Santi et al., all patients expressed IgG4 while only three of seven patients expressed IgG1, IgG3, and IgG4.3 IgG1 and IgG3 have a higher affinity for complement and may explain the variable prevalence of complement on DIF in our cohort and that reported by Maciejowska et al.6 The significance of linear IgA in the basement membrane zone in our patient (case 3) is unclear. Interestingly a recent case report has described concomitant BP and PH in the same patient and should serve to alert the physician of evolving or additional pathologies.15 Corticosteroids would appear to be universally effective, although high doses may be required. All patients treated with sulfonamides (four patients) demonstrated at least a partial response. Monotherapy with dapsone was possible in two patients. Cases 1, 7, and 8 are of particular interest because the patients received rituximab. Rituximab has proven highly effective in the treatment of pemphigus in a recent clinical trial, predominantly for treatment of PV.16 While we await a review in one patient, the first two patients to receive rituximab in our cohort failed to demonstrate a marked clinical response. Other therapies partially effective in our cohort included IVIG (n = 2), azathioprine (n = 2), or leflunomide (n = 1). Maciejowska et al.6 reported disease control in seven of 15 patients using dapsone and prednisone. Five patients required prednisone and cyclophosphamide or azathioprine. Two patients were controlled with prednisone only, and a single patient was controlled with diasone. Santi et al.3 reported treatment with only oral corticosteroid in seven patients. Morini et al.4 reported a further cohort of seven patients treated predominantly with oral corticosteroids and methotrexate. The evidence base for treatment of PH is limited by the small sample sizes. Based on our experience and review of the literature, we recommend corticosteroids are utilized first line with consideration of dapsone or sulfasalazine thereafter. Other immunosuppressive agents used in the treatment of pemphigus are likely to have a role but remain to be determined. Several subtypes of pemphigus are described in the literature, and clinical distinction should be made where possible. Table 3 provides an overview of important features of PV, PF, and PH. PH may evolve into either PV or PF.3,6 While it would appear that most patients with International Journal of Dermatology 2015

PH express Dsg-1 and have a tendency to develop features more compatible with PF, it is clear this is not universal. Indeed, in our cases the observation of suprabasal acantholysis and previous history of PV, suggest a phenotype of PV. This case series has several limitations. This is a retrospective chart review, and therefore an inherently selfselected group. Additionally we did not analyze Dsg antibodies. Despite these limitations, our case series serves to further understanding of the presentation, diagnosis, and management of PH. Intense pruritus in the context of an urticated erythema, with a variable vesiculobullous eruption, and the absence of mucosal involvement should prompt consideration of the diagnosis. Urticated erythema, in partially treated or early disease, may be impossible to distinguish on clinical grounds from pre-BP. In this clinical context, DIF is central to confirming the diagnosis. Evolution of the disease over time may result in clinical and histological features more compatible with PF, or less commonly PV. Given the challenge of diagnosing PH, the potential to misdiagnose the condition is significant. Therapeutically the role of corticosteroids and sulfonamides appears valid and reinforces the need for accurate diagnosis. However, where sulfonamides are insufficient for disease control, standard therapies for PV may be utilized. References 1 Jablonska S, Chorzelski TP, Beutner EH, et al. Herpetiform pemphigus, a variable pattern of pemphigus. Int J Dermatol 1975; 14: 353–359. 2 Burns T, Breathnach S, Cox N, et al. Rook’s Textbook of Dermatology, 8th edn. Chichester, West Sussex: WileyBlackwell, 2010. 3 Santi CG, Maruta CW, Aoki V, et al. Pemphigus herpetiformis is a rare clinical expression of nonendemic pemphigus foliaceus, fogo selvagem, and pemphigus vulgaris. Cooperative Group on Fogo Selvagem Research. J Am Acad Dermatol 1996; 34: 40–46. 4 Morini JP, Jomaa B, Gorgi Y, et al. Pemphigus foliaceus in young women. An endemic focus in the Sousse area of Tunisia. Arch Dermatol 1993; 129: 69–73. 5 Matsukura S, Knowles SR, Walsh S, et al. Effect of a single-cycle alternative dosing regimen for rituximab for recalcitrant pemphigus: a case series of 9 patients. Arch Dermatol 2012; 148: 734–739. 6 Maciejowska E, Jablonska S, Chorzelski T. Is pemphigus herpetiformis an entity? Int J Dermatol 1987; 26: 571–577. 7 Duarte IB, Bastazini I Jr, Barreto JA, et al. Pemphigus herpetiformis in childhood. Pediatr Dermatol 2010; 27: 488–491. 8 Bystryn JC, Rudolph JL. Pemphigus. Lancet 2005; 366: 61–73. ª 2015 The International Society of Dermatology

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9 Dias M, dos Santos AP, Sousa J, et al. Herpetiform pemphigus. J Eur Acad Dermatol Venereol 1999; 12: 82–85. 10 Tateishi C, Tsuruta D, Nakanishi T, et al. Antidesmocollin-1 antibody-positive, antidesmoglein antibody-negative pemphigus herpetiformis. J Am Acad Dermatol 2010; 63: e8–e10. 11 Robinson ND, Hashimoto T, Amagai M, et al. The new pemphigus variants. J Am Acad Dermatol 1999; 40: 649–671. quiz 672–673. 12 Ishii K, Amagai M, Komai A, et al. Desmoglein 1 and desmoglein 3 are the target autoantigens in herpetiform pemphigus. Arch Dermatol 1999; 135: 943–947. 13 Sekiguchi M, Futei Y, Fujii Y, et al. Dominant autoimmune epitopes recognized by pemphigus

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antibodies map to the N-terminal adhesive region of desmogleins. J Immunol 2001; 167: 5439–5448. 14 Amagai M, Karpati S, Prussick R, et al. Autoantibodies against the amino-terminal cadherin-like binding domain of pemphigus vulgaris antigen are pathogenic. J Clin Invest 1992; 90: 919–926. 15 Ohata C, Koga H, Teye K, et al. Concurrence of bullous pemphigoid and herpetiform pemphigus with IgG antibodies to desmogleins 1/3 and desmocollins 1-3. Br J Dermatol 2013; 168: 879–881. 16 Leshem YA, Hodak E, David M, et al. Successful treatment of pemphigus with biweekly 1-g infusions of rituximab: a retrospective study of 47 patients. J Am Acad Dermatol 2013; 68: 404–411.

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Pemphigus herpetiformis: a case series and review of the literature.

Pemphigus herpetiformis (PH) is a rare subtype of pemphigus that presents challenges in diagnosis...
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