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Pemphigus vegetans Neumann type with anti-desmoglein and anti-periplakin autoantibodies

European Journal of Dermatology. Volume 17, Number 6, 530-3, November-December 2007, Clinical report

DOI : 10.1684/ejd.2007.0270

Summary

Author(s) : Emanuele Cozzani, Konstantina Christana, Alessandro Mastrogiacomo, Paolo Rampini, Massimo Drosera, Massimo Casu, Giovanni Murialdo, Aurora Parodi , Section of Dermatology, University of Genoa, Viale Benedetto XV, n. 7, 16132 Genova Italy, Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell’Immacolata IRCCS, Rome, Italy, Section of Endocrinology, University of Genoa, Italy.

Summary : Pemphigus vegetans is a rare variant of pemphigus vulgaris characterized by vegetating lesions in the folds and mouth and by the presence of autoantibodies against desmoglein 3. We describe two Caucasian patients with pemphigus vegetans, one of them presented antibodies to desmoglein 3 and 1 and the other one to desmoglein 3. Both patients also had circulating antibodies against a 190 kDa protein co-migrating with periplakin. Anti-periplakin reactivity is usually detected in paraneoplastic pemphigus, while it has never been reported in pemphigus vegetans. Our observation enlarges the spectrum of autoantibodies which may be associated with pemphigus vegetans. However, the pathophysiological significance of anti-periplakin reactivity in this pemphigus variant remains to be determined.

Keywords : desmoglein 1, desmoglein 3, periplakin, autoantibodies, pemphigus vegetans

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Auteur(s) : Emanuele Cozzani¹, Konstantina Christana¹, Alessandro Mastrogiacomo², Paolo Rampini¹, Massimo Drosera¹, Massimo Casu³, Giovanni Murialdo³, Aurora Parodi¹

¹Section of Dermatology, University of Genoa, Viale Benedetto XV, n. 7, 16132 Genova Italy
²Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell’Immacolata IRCCS, Rome, Italy
³Section of Endocrinology, University of Genoa, Italy

accepté le 30 Mai 2007

Pemphigus vegetans (PVeg) is an uncommon variant of pemphigus vulgaris, comprising less than 1-2% of all cases of pemphigus, characterized by vegetating lesions primarily localised to flexural areas [1]. Clinically two subtypes are recognized: Neumann PVeg and Hallopeau PVeg [2, 3]. The first subtype was described in 1876 by Neumann as a disease characterized by bullae that extend and coalesce, evolving to vegetating masses. In time, the vegetations become dry, hyperkeratotic and fissured. The second subtype was described in 1889 by Hallopeau as a new skin disease characterized by a polycyclic eruption of pustules that form firm pink papillomas which progressively flatten and change to dark brown plaques. Involvement of the oral mucosa is almost invariable in both subtypes. Hallopeau PVeg has a relatively benign course and spontaneous remission is possible. The Neumann subtype is more common, it develops extensive lesions and is often refractory to therapy. We describe 2 patients in whom the clinical and histological features and the disease course were typical of PVeg Neumann subtype. These patients presented antibodies directed to desmoglein (Dsg) 3 and 1 and to Dsg3, respectively. In addition, both patients had circulating autoantibodies against a 190 kDa protein co-migrating with periplakin.

Case reports

Case 1. A 72-year-old man, affected by diabetes mellitus type II, presented with a 1.5-year history of vegetating, malodorous, violaceous plaques in the axillary and inguinal folds (figure 1A) and erosions of the oral mucosa, tongue and perioral area. The cutaneous lesions started with vesicles and bullae that extended peripherally, forming later the vegetating lesions. Laboratory routine tests were within normal limits except for glycated haemoglobin that was elevated (7.3%, normal value 4.3-5.8%). A skin biopsy showed hyperplasia of the epidermis with suprabasal acantholysis and an inflammatory dermal infiltrate composed of lymphocytes, eosinophils and neutrophils (figure 2). Direct immunofluorescence (DIF) showed the deposition of IgG in intercellular spaces of the epidermis and granular deposits of C3 at the basal membrane zone (BMZ). Circulating pemphigus autoantibodies (Ab) were found at a titre of 1:1280 using both monkey oesophagus and rat bladder as substrates. Immunoblotting (IB) analysis with epidermal extracts from normal human skin demonstrated bands at 130 kDa antigen (Dsg3) and 190 kDa, the latter comigrating with an anti-periplakin polyclonal antibody (C-20, Santa Cruz Biotechnology, Santa Cruz, USA) (figure 3). Anti-Dsg enzyme-linked immunosorbent assay (ELISA) was positive for anti-Dsg1 (187,44 U/L; cut-off < 20) and anti-Dsg3 (199,60 U/L; cut off < 20).

Case 2. A 77-year-old woman came to our observation with a 1-year history of itchy, vegetating, violaceous plaques, confined to the intertriginous regions (figure 1B) and preceded by vesicles and bullae. The patient also presented erosions on the palate and hemorrhagic crusts on the lips and nasal nostrils. A skin biopsy showed epidermal hyperplasia with acantholysis and a dermal infiltrate of eosinophils, neutrophils and monocytes. DIF examination revealed deposition of IgG and C3 in the intercellular spaces of the epidermis and linear deposits of C3 along the BMZ. Circulating pemphigus Ab binding to monkey oesophagus and rat bladder epithelium were found at a titre of 1:640. IB demonstrated a band at 130 kDa antigen (Dsg3) and a faint band at 190 kDa, comigrating with an anti-periplakin polyclonal antibody. Dsg ELISA was positive for anti-Dsg3 (248 U/L; cut-off < 20) but negative for anti-Dsg1.

In both patients, evaluation for an associated malignancy including chest radiography, abdomen echography, full blood count and serum tumour markers (carcinoembryonic antigen and cancer antigens 19-9, 15-3 and 125) failed to reveal any occult solid tumour or lymphoproliferative disorder over a 2-year follow-up.

On the basis of the clinical and laboratory findings, a diagnosis of Pveg Neumann type was made in the two patients. The first one started treatment with prednisone (50 mg/day) and azathioprine (50 mg/day) and the second one with prednisone (60 mg/day). Both patients clearly improved within one month, but both had a relapse. The first patient relapsed 6 months later when the dosage of prednisone was 12.5 mg/day, and the second one 7 months later while being treated with prednisone 10 mg/day. The dosage of prednisone was then increased to 25 mg/day with disease control.

Discussion

In our two PVeg patients, the IIF positivity on rat bladder epithelium together with the presence of circulating antibodies recognizing a 190 kDa band co-migrating with periplakin and of C3 deposits along the BMZ raised the possible diagnosis of paraneoplastic pemphigus (PNP). However, this was excluded by the lack of any evidence of malignancy at the time of diagnosis and over a 2-year follow-up period. Additional findings against the PNP diagnosis included the absence of IgG deposition along the BMZ on DIF examination and the lack of reactivity by IB against other proteins of the antigen complex recognized by PNP sera, in particular envoplakin [4, 5].

PVeg patients are reported to present antibodies directed to Dsg3 [1, 6, 7], and our patients were no exceptions. The reactivity against Dsg1 detected by ELISA in the first patient is also not surprising as Pveg is a clinical variant of PV in which anti-Dsg1 Ab often accompany anti-Dsg3 Ab. In addition, PVeg sera have previously been reported to recognise Dsg1 [8]. In our patient, the absence of reactivity against Dsg1 using IB on epidermal extracts could probably be explained by the lower sensitivity of this technique as compared to ELISA [9, 10]. An interesting and unexpected finding in our PVeg cases was the presence of reactivity against a 190 kDa protein co-migrating with periplakin. Periplakin belongs to the plakin family of cytoplasmic molecules involved in the link between desmosomal and hemidesmosomal components and cytoskeleton intermediate filaments [11]. IB reactivity against periplakin and/or envoplakin is regularly detected in PNP and has been reported by Joly et al. to represent a highly specific feature for this disease [4, 5]. However, in a subsequent study, Nagata et al. [12] examined 240 non-PNP sera (pemphigus vulgaris, foliaceus, bullous pemphigoid) by IB on epidermal extracts and found that 19% of non-PNP sera reacted with a protein co-migrating with periplakin. Moreover, they showed that most non-PNP sera reactive with periplakin using epidermal extracts, also recognised periplakin recombinant proteins. Other authors have also described the presence of anti-periplakin circulating antibodies in pemphigus foliaceous [13]. Therefore, the 190 kDa protein band recognised by our PVeg sera is most likely periplakin, although we cannot rule out the possibility that an as yet uncharacterized 190 kDa protein is targeted in these patients. Recently, the presence of circulating Ab recognising periplakin has also been detected by IB, using both epidermal extracts and recombinant proteins, in the sera of 10 out of 10 patients affected with toxic epidermal necrolysis [14]. Furthermore, a reactivity to different antigens of the plakin family has been described in blistering skin diseases other than PNP. In fact, autoantibodies directed to desmoplakins were found in two patients with pemphigus vulgaris and pemphigus foliaceus [15, 16], in three patients with mucosal dominant pemphigus vulgaris [17], in two patients with bullous pemphigoid [18, 19] and in six patients with erythema multiforme major [20]. Finally, in a recent study we have shown that circulating antibodies to desmoplakins I and II can be detected in pemphigus vulgaris sera, especially when the cutaneous involvement is extensive [21].

The IIF positivity on rat bladder epithelium in our two PVeg patients most probably correlates with the presence of anti-periplakin antibodies and further confirms that rat bladder is a sensitive substrate for detecting anti-plakin antibodies, although not specific enough by itself to permit the diagnosis of PNP. In fact, a positive labelling on rat bladder has been found in some patients affected by pemphigus vulgaris presenting anti-desmoplakin antibodies and in toxic epidermal necrolysis with anti-periplakin antibodies [14, 17, 21].

As suggested for other pemphigus variants, anti-periplakin antibodies in PVeg might result from an epitope spreading phenomenon. However, the pathophysiological role of antibodies directed against molecules other than Dsg is currently unknown. Further studies on a larger number of PVeg patients should allow us to verify if anti-periplakin antibodies are a marker of PVeg.

Acknowledgements

Financial support: none. Conflict of interest: none.

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