Case Report

Transition from Pemphigus Vulgaris to Pemphigus Foliaceus

- Report of Two Cases
Po-Yu Shih
1

Tseng-Tong Kuo

2, 4

Chien-Chun Chiou Jia-Ru Wang Ke-Jen Yu 1, 4 1, 4 Hong-Shang Hong Yue-Zon Kuan

Hsin-Chun Ho

3, 4

Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are two different subtypes of the pemphigus group with distinct clinicopathologic features. Clinically, PV presents with mucosal, mucocutaneous, or cutaneous lesions whereas PF lesions are primarily cutaneous. Histopathologically, intraepidermal acantholysis is located at the granular layer in PF and suprabasally in PV. Traditionally, these differences are used for basis of treatment selection and prognostic estimation. However, infrequent transition between the subtypes has been reported. Herein we describe two cases of PV with transition into PF and discuss the proposed mechanism for this phenomenon. (Dermatol Sinica 27: 52-58, 2009)

Key words: Pemphigus, Desmoglein, Subtype transition, Epitope spreading

INTRODUCTION Pemphigus is one of the prototypical autoimmune bullous diseases. It has been divided into two distinct groups depending on the location of the vesicle in the epidermis.1 Traditionally, this simplified dichotomous classification into pemphigus vulgaris (PV) and pemphigus foliaceus (PF) by histopathology can be reflected clinically in their differing presentation, lesional distribution, expected disease prognoses, and treatment protocols. Despite these differences, the mechanisms of disease are believed to be similar. Concurrent presentation or transition between pemphigus phenotypes have been reported previously, but is a relatively infrequent phenomenon.1-8 As of 2006, less

than 25 cases had been reported.9 Herein we report two cases of pemphigus vulgaris with transition into pemphigus foliaceus.

CASE REPORT CASE 1 A 38-year-old man with hepatitis B virus-related liver cirrhosis, Child class C, presented in March 2002 with recurrent eruptions over the trunk and limbs of 6 months duration. Family history and contact history were unremarkable. These itchy vesicles and erosions over the trunk and limbs had been treated at a local medical clinic, but did not improve significantly (Fig. 1A). New oral ulcers then occurred. A skin biopsy was performed on his back under the clinical

From the Departments of Dermatology1 and Pathology,2 Chang Gung Memorial Hospital, Linkou, Taiwan and Department of Dermatology,3 Chang Gung Memorial Hospital, Keelung, Taiwan and Chang Gung University College of Medicine4 Corresponding author: Hsin-Chun Ho, MD, Department of Dermatology, Chang Gung Memorial Hospital, 199 Tun-Hwa North Road, Taipei 105, Taiwan TEL: 886-2-27135211 FAX: 886-2-27191623 E-mail: david@adm.cgmh.org.tw Funding source: none Conict of interest: none declared Received: April 23, 2008 Revised: June 19, 2008 Accepted: October 23, 2008

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D Fig. 1
(A) Initial presentation in March 2002 with multiple itchy erythematous plaques and erosions with flaccid bullae over the trunk. (B) Histopathology revealed suprabasal acantholysis and acantholytic vesicle formation with perivascular mononuclear cell infiltrates. (H&E, original magnification x100) (C) Consultation during admission for acute hepatitis in August 2006. A large erosive plaque with whitish crust and debris is noted over the nasal tip. A small itchy erythematous papule/vesicle is noted over the left cheek. Note prominent icterus. (D) Superficial acantholysis of the granular layer. (H&E, original magnification x40) (E) Follow-up in March 2007 (6 months later). The nasal tip erosion was no longer evident after treatment with topical corticosteroid cream.

diagnosis of bullous dermatosis, favoring PV. Histopathologic examination revealed

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suprabasal acantholysis with formation of an intraepidermal vesicle and mild perivascular

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mononuclear cell infiltrates with occasional eosinophils in dermis (Fig. 1B). Direct immunofluorescence revealed positive intercellular IgG and C3 staining, further supporting the diagnosis of PV. Treatment was initiated with oral prednisolone 75 mg/day (equal to 1 mg/ kg/day) and topical betametasone 0.12% + gentamicin 0.1% cream b.i.d. The dose was tapered gradually to 5 mg/day (0.067 mg/kg/ day) over a years time. This maintenance dose was further tapered to 5 mg q.o.d. two months later. However, persistent cough was noted, and after thorough laboratory examination, pulmonary tuberculosis (TB) infection was diagnosed 16 months after initial onset of skin lesions. Anti-TB drugs were added, but toxic hepatitis was noted (ALT: 1296 U/L, AST: 791 U/L) two months later, and thus TB treatment was changed to monotherapy with ciprofloxacin, which lasted for one month. Thereafter, the patient was only followed in gastroenterology clinic; another episode of acute hepatitis due to hepatitis B virus reactivation was noted one year later (November 2004). In July 2006, some itchy facial lesions appeared, but no new treatment was sought. By August 2006, he was admitted to gastroenterology again for liver function impairment and deepening jaundice, under the impression of impending liver decompensation, possibly due to HBV-reactivation. A dermatology consultation was requested, and the patient was assessed for his facial lesions. On physical examination, a 3x3 cm oozing erosion with thickened crust over the nasal tip and a crusted erythematous papule over the left cheek were noted (Fig. 1C). This episode had begun 3 months before with the shallow erosion over the nasal tip, then spreading to the cheek about one week ago in the form of an erythematous papule. No oral ulcers or other lesions on the trunk or extremities were noted. Since the patient had a history
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of pemphigus vulgaris, pemphigus vegetans was suspected. However, as anti-intercellular substance antibody (anti-ICS Ab) was negative, another skin biopsy was performed. Histopathologic examination revealed focal superficial acantholysis of the granular cells and mild perivascular and focal perifollicular mononuclear cell infiltrates with occasional neutrophils. Acantholysis of granular cells was also seen in follicular lumina (Fig. 1D). Direct immunofluorescence revealed positive intercellular IgG and C3 staining. The diagnosis of PF was made. Since the general status of the patient was poor (liver decompensation possibly due to HBV-reactivation, and growth of Aeromonas hydrophilia in blood culture), systemic corticosteroids were contraindicated. Moderate-potency topical corticosteroid therapy was chosen due to the localized involvement and non-progressive nature of the PF lesions. By follow-up in March 2007 later, the lesions had completely resolved (Fig. 1E). CASE 2 A 48-year-old woman admitted for diabetic ketoacidosis presented in March 1992 for evaluation of relapsing blisters on the entire body for more than one years duration. These generalized blisters had been treated at another hospital as bullous pemphigoid, although no skin biopsy had been performed for definitive diagnosis. On physical examination, there were flaccid vesicles over the central abdomen, erythematous patches with tiny patches over the thighs, postinflammatory hyperpigmentation on wrists and one new tense vesicle over the left forearm. Severe itching was complained. There were no oral ulcers or other skin lesions. A skin biopsy of the left forearm vesicle was performed under the clinical impression of bullous pemphigoid or linear IgA dermatosis. Histopathologic examination revealed an intraepidermal vesicle containing acantholytic
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mg/day, equal to 1.5mg/kg/day). The corticosteroid dose had been tapered down to a maintenance dose of 25 mg/day three months later when she was once again admitted due to diabetic ketoacidosis. From this admission onward, skin biopsies from 6 different locations over the next 6 years, all revealed superficial acantholysis of granular cells (Fig. 2B) and PF diagnosed each time. During this span, only one anti-ICS Ab examination (in June 1992) showed low titers (1:20); the subsequent 13 examinations showed consistently elevated titers ranging from 1:160~1:1280. This correlated with the progressively intractable disease despite aggressive treatment with high dose of systemic corticosteroids (up to dexamethasone 12 mg/day; equivalent to prednisolone 1.25mg/kg/day), and adjuvant immunotherapy with azathioprine, vibramycin, and multiple courses of plasmapheresis. She was lost to follow-up 2 months after her last admission in February 1998.

B Fig. 2
(A) Histopathology in March 1992, at 6 months after initial onset. An intraepidermal vesicle containing acantholytic cells and many eosinophils with fibrinous fluid accumulation, favoring pemphigus vulgaris. (H&E, original magnification x100) (B) Acanthosis and superficial acantholysis of the granular cell layer with perivascular mononuclear cell infiltrates in dermis. Pemphigus foliaceus was diagnosed. (H&E, original magnification x100)

cells and many eosinophils with fibrinous fluid. Eosinophils and mononuclear cells were also noted in dermis (Fig. 2A). Direct immunofluorescence revealed positive intercellular IgG staining, and the diagnosis of PV was made. Anti-ICS Ab was also checked; it was 1:160 (+). High-dose systemic corticosteroids were initiated (prednisolone 90
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DISCUSSION Although both PV and PF are characterized by intraepidermal acantholysis with vesicle formation, they can be distinguished clinically and histopathologically. Clinically PV involves both the epidermis and/or the mucosa while PF affects only the skin.10 The differing sites of involvement noted clinically can be elegantly explained by the theory of desmoglein compensation.11 Desmogleins (Dsg) along with desmocollins are the two groups of cadherins or desmosomecell specific adhesion molecules which comprise the keratinocytic desmosomes.12 Dsg 3 is believed to be the main cadherin present in mucosa, whereas Dsg 1 is likely the major component of the epidermal desmosomes, although Dsg 3 probably also plays a role in skin adhesion. Therefore it has been proposed that the profile of autoantibodies to desmogleins is the primary determinant of clinical phenotype with antibodies to Dsg
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3 being associated with mucosa-dominant pemphigus, whereas the presence of both anti-Dsg 3 and anti-Dsg 1 is associated with mucocutaneous pemphigus.13 Although minor cutaneous involvement was observed in most anti-Dsg3+/Dsg1- patients, severe cutaneous involvement was seen only in anti-Dsg3+/ Dsg1+ patients.14 PF, by similar logic, is associated with an anti-Dsg3-/Dsg1+ profile and presents primarily with skin lesions. 15 This has been confirmed by large scale studies using enzyme-linked immunosorbent assay (ELISA),13-18 suggesting anti-Dsg ELISA testing may be a viable alternative diagnostic tool in conjunction to the histopathological analysis. The role of desmoglein antibodies have further been supported by recent reports of altering desmoglein titers in patients with transition in pemphigus phenotypes. 3-9 Serial testing of anti-Dsg 1 and Dsg 3 antibody titers in patients with PV transitions into PF have revealed decreasing anti-Dsg 3 antibody level with relatively stable levels of anti-Dsg 1 antibody titers.3, 6 Nevertheless, a delay of about one year between conversion of PV to PF phenotype and the decrease of anti-Dsg 3 antibodies levels to sub-threshold levels was observed in one patient.3 In the reported cases, a change from PV to PF is more common than a change from PF to PV.7 Nevertheless, antibody profiles in observed PF shifts into PV revealed antibody profile transition from anti-Dsg3-/Dsgl+ to anti-Dsg3+/Dsgl+, in concordance with the proposed mechanism.4, 5 The mechanism for such an acquisition of new autoantibodies has been termed epitope spreading in continuous transitions and epitope shift in patients with prolonged inactive disease states5 by which transitions between different pemphigus phenotypes as well as into bullous pemphigoid have been explained.19, 20 Namely, tissue damage caused by an autoimmune or inflammatory skin disease exposes a previously sequestered antigen normally undetectable by the immune
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system, leading to the production of autoantibodies against the exposed protein components and formation of another autoimmune skin disease.20, 21 In our first patient, systemic corticosteroids were clearly contraindicated considering his Aeromonas septicemia, impending liver decompensation, and suspected hepatitis B virus reactivation. Given his limited involvement and the phenotype of PF topical betamethasone and gentamicin cream was selected. Clinical resolution was noted at 6 months follow-up. In our 2nd patient, the elevated activity and widespread involvement of PF necessitated the use of systemic immunosuppressants, and even then, clinical progression was seen. Thus the optimal therapeutic route and dose may depend a variety of factors, although the extent of involvement (indicative of disease activity) is probably the most important. Thus while systemic glucocorticoids are the mainstay of therapy for pemphigus as a whole, in select patients with localized PF, moderate-to-high potency corticosteroids can be used as an initial therapy.11 As prognosis between the different subtypes have been shown to be of little significance , some localized PV may likely be treatable, at least initially, via the topical route. In terms of the prognostic implications of pemphigus with subtype transition, further study may be needed since this phenomenon may be a manifestation of selective inhibition or epitope spreading.

ACKNOWLEDGEMENTS We would like to thank Dr. Meng-Yun Hsieh for her editorial assistance. REFERENCES

1. Feliciani C, Motta A, Castellaneta M, et al. : Coexisting pemphigus vulgaris and pemphigus foliaceus in the same patient. Int J Dermatol 44: 139-141, 2005. 2. Muller E, Kernland K, Caldelari R, et al.: Un56

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usual pemphigus phenotype in the presence of a Dsg1 and Dsg3 autoantibody profile. J Invest Dermatol 118: 551-555, 2002. 3. Harman KE, Gratian MJ, Bhogal BS, et al.: The transition of pemphigus vulgaris into pemphigus foliaceus: a reflection of changing desmoglein 1 and 3 autoantibody levels in pemphigus vulgaris. Br J Dermatol 146: 684-687, 2002. 4. Ishii K, Amagai M, Ohata Y, et al.: Development of pemphigus vulgaris in a patient with pemphigus foliaceus: antidesmoglein antibody profile shift confirmed by enzyme-linked immunosorbent assay. J Am Acad Dermatol 42: 859-861, 2000. 5. Kimoto M, Ohyama M, Hata Y, et al.: A Case of pemphigus foliaceus which occurred after five years of remission from pemphigus vulgaris. Dermatology 203: 174-176, 2001. 6. Tsuji Y, Kawashima T, Yokota K, et al.: Clinical and serological transition from pemphigus vulgaris to pemphigus foliaceus demonstrated by desmoglein ELISA system. Arch Dermatol 138: 95-96, 2002. 7. Toth GG, Pas HH, Jonkman MF: Transition of pemphigus vulgaris into pemphigus foliaceus confirmed by antidesmoglein ELISA profile. Int J Dermatol 41: 525-527, 2002. 8. Park SG, Chang JY, Cho YH, et al.: Transition from Pemphigus Foliaceus to Pemphigus Vulgaris: Case Report with Literature Review. Yonsei Med J 47: 278-281, 2006. 9. Ng PPL, Thng STG: Three cases of transition from pemphigus vulgaris to pemphigus foliaceus confirmed by desmoglein ELISA. Dermatology 210: 319-321, 2005. 10. Rivitti EA, Sanches JA, Miyauchi LM, et al. : Pemphigus foliaceus autoantibodies bind both epidermis and squamous mucosal epithelium, but tissue injury is detected only in the epidermis. The Cooperative Group on Fogo Selvagem Research. J Am Acad Dermatol 31: 954-958, 1994. 11. Stanley JR: Pemphigus. In: Freedberg IM, Eisen AZ, Wolff K, et al., eds.: Fitzpatricks Dermatology in General Medicine. 6th ed. New York: McGraw-Hill, 558-567, 2003. 12. Wu H, Schapiro B, Harrist TJ: Noninfectious vesiculobullous and vesiculopustular diseases. In: Elder DE, Elenitsas R, Johnson BL, et al.,

eds.: Levers Histopathology of the Skin. 9th ed. Philadelphia: Lippincott Williams and Wilkins, 243-291, 2005. 13. Jamora MJJ, Jiao D, Bystryn JC: Antibodies to desmoglein 1 and 3, and the clinical phenotype of pemphigus vulgaris. J Am Acad Dermatol 48: 976-977, 2003. 14. Harman KE, Gratian MJ, Bhogal BS, et al.: A study of desmoglein 1 autoantibodies in pemphigus vulgaris: racial differences in frequency and the association with a more severe phenotype. Br J Dermatol 143: 343-348, 2000. 15. Amagai M, Tsunoda K, Zillikens D, et al.: The clinical phenotype of pemphigus is defined by the anti-desmoglein autoantibody profile. J Am Acad Dermatol 40: 167-170, 1999. 16. Komai A, Amagai M, Ishii K, et al.: The clinical transition between pemphigus foliaceus and pemphigus vulgaris correlates well with the changes in autoantibody profile assessed by an enzyme-linked immunosorbent assay. Br J Dermatol 144: 1177-1182, 2001. 17. Huang CH, Chen CC, Wang CJ, et al. : Using desmoglein 1 and 3 enzyme-linked immunosorbent assay as an adjunct diagnostic tool for pemphigus. J Chin Med Assoc 70: 65-70, 2007. 18. Cheng SW, Kobayashi M, Tanikawa A, et al. : Monitoring disease activity in pemphigus with enzyme-linked immunosorbent assay using recombinant desmogleins 1 and 3. Br J Dermatol 147: 261-265, 2002. 19. Maeda JY, Moura AKA, Maruta CW, et al. : Changes in the autoimmune blistering response: a clinical and immunopathological shift from pemphigus foliaceus to bullous pemphigoid. Clin Exp Dermatol 31: 653-655, 2006. 20. Peterson JD, Chang AJ, Chan LS: Clinical evidence of an intermolecular epitope spreading in a patient with pemphigus foliaceus converting into bullous pemphigoid. Arch Dermatol 143: 272274, 2007. 21. Chan LS, Vanderlugt CJ, Hashimoto T: Epitope spreading: Lessons from autoimmune diseases. J Invest Dermatol 110: 103-109, 1998. 22. Zaraa I, Mokni M, Hsairi M, et al.: Pemphigus vulgaris and pemphigus foliaceus: similar prognosis? Int J Dermatol 46: 923-926, 2007.

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