British Journal of Dermatology 2000; 142: 812±851. Correspondence A case of paraneoplastic pemphigus with antidesmoglein 1 antibodies as determined by immunoblotting Sir, Paraneoplastic pemphigus (PNP) is a subset of pemphigus in patients with neoplasia, in which clinical and histological features of pemphigus vulgaris (PV) are variably associated with features of erythema multiforme, bullous pemphigoid and lichen planus.1 PNP autoantibodies are directed against an antigen complex mainly composed of proteins of the plakin family: these are major components of desmosomal and hemidesmosomal plaques. We first described the presence of antidesmoglein 3 (Dsg3) antibodies in PNP sera by immuno- blotting.2 It has recently been demonstrated that pathogenic anti-Dsg3 autoantibodies can be consistently detected in PNP sera by enzyme-linked immunosorbent assay (ELISA).3 Curiously, whereas antidesmoglein 1 (Dsg1) antibodies have been recovered in more than 50% of PNP sera using ELISA, such autoantibodies have never been detected in PNP sera using immunoblotting or immunoprecipitation assays. We describe a PNP patient with an atypical clinical presentation in whom circulating anti-Dsg1 antibodies were detected by immunoblotting. A 70-year-old man with a history of chronic lymphoid leukaemia and prostate carcinoma presented with a generalized lichenoid eruption. Cutaneous lesions evolved to an exfoliative erythroderma (Fig. 1a) associated with atypical target-like lesions on the lower limbs. The patient had mucosal erosions and extensive cutaneous blisters with a positive Nikolsky sign. He died of infection despite parenteral antibiotics and corticoid therapy. Histological examination of a cutaneous blister showed basilar and suprabasilar cleavage with vacuolar changes and keratinocyte necrosis. Direct and indirect immunofluorescence (IF) showed antiepidermal cell surface antibodies without antibasement membrane zone antibodies. The patient's serum stained rat bladder epithelium on indirect IF. Immunoblot analysis2 showed IgG antibodies directed against bands of 250-, 210-(doublet) and 190-kDa molecular weight, corresponding to desmoplakin I, envo- plakin and desmoplakin II, and periplakin, respectively. Additionally, the patient's serum contained IgG antibodies that recognized a 160-kDa band comigrating with the band recognized by a murine anti-Dsg1 monoclonal antibody (Clone DG3.10, Progen, Heidelberg, Germany) (Fig. 1b). It is surprising that, to date, anti-Dsg1 antibodies have never been detected in PNP sera by immunoblotting or immunoprecipitation, whereas they have recently been Figure 1. (a) Paraneoplastic pemphigus presenting as an exfoliative reported in 50% of PNP sera by an ELISA assay using 3 erythroderma, with erosions and necrolysis. (b) Immunoblot analysis baculovirus-expressed recombinant Dsg1. One possible of the patient's serum on human epidermal extract. Lane A, murine explanation is that PNP sera, like pemphigus foliaceus (PF) antidesmoglein 1 monoclonal antibody; lane B, patient's serum sera, may recognize a conformational epitope on Dsg1 which revealed with a goat antihuman IgG antibody; lane C, control serum is denatured during the immunoblotting extraction pro- from a pemphigus foliaceus patient; lane D, control serum from a cedure. The pathogenic effect of PNP anti-Dsg1 antibodies pemphigus vulgaris patient; lane E, control serum. 812 q 2000 British Association of Dermatologists CORRESPONDENCE 813 remains uncertain. The exfoliative erythroderma in our 4 Hashimoto T, Amagai M, Wang N et al. Novel non-radioisotope patient is consistent with a pathogenic role for this auto- immunoprecipitation studies indicate involvement of pemphigus antibody as it can be seen in patients with PF. In contrast, it vulgaris antigen in paraneoplastic pemphigus. J Dermatol Sci 1998; has recently been demonstrated that the pathogenic effect of 17: 132±9. PNP sera containing both anti-Dsg1 and anti-Dsg3 antibodies was abolished by specific adsorption of anti-Dsg3 antibodies, suggesting that the remaining anti-Dsg1 antibodies present in the PNP sera were not pathogenic.3 The presence of mucosal A vesicular bullous pemphigoid with an autoantibody lesions in our patient and the histological suprabasilar against plectin cleavage suggested the presence of pathogenic anti-Dsg3 antibodies. Such an antibody population could not be Sir, Bullous pemphigoid (BP) is an autoimmune blistering detected in the patient's serum by immunoblotting. However, disease in which the epidermis is separated from the dermis at such anti-Dsg3 antibodies are not consistently detected in the level of the lamina lucida of the basement membrane PNP sera by immunoblotting,3,4 whereas they are con- zone. The lesions are characterized by large and tense bullae sistently detected by ELISA.3 Finally, the demonstration of up to several centimetres in diameter developing on erythe- anti-Dsg3 and/or anti-Dsg1 antibodies in sera from patients matous or apparently normal skin. Patient sera react with with PNP, PV and PF suggests a common mechanism of two major components, 230- and 180-kDa BP antigens breakdown of immunological tolerance against desmogleins (BPAg1 and BPAg2) at the dermoepidermal junction.1 Several in these types of pemphigus, and confirms the role of anti- atypical variants of BP have been reported. These include Dsg3 and possibly of anti-Dsg1 antibodies in the pathogenesis polymorphic, localized, cicatricial and vesicular2 pemphigoid. of PNP. The lesions of vesicular pemphigoid are characterized by multiple small tense vesicles with a symmetrical distribution. Clinique dermatologique, P. M ARTEL In some cases of vesicular pemphigoid, heterogeneous HoÃpital Charles Nicolle, D.GILBERT* autoantibodies against 205- and 105-kDa polypeptides in 3 1 rue de Germont, B.LABEILLE² addition to the 180-kDa BP antigen have been reported. A 76031 Rouen cedex, J.KANITAKIS³ unique subepidermal blistering disease that resembles BP France P. J OLY both clinically and immunohistopathologically has been *Laboratoire d'immunopathologie clinique et reported. Immunoblot analysis revealed that the patient expeÂrimentale, serum did not react with the 230- or 180-kDa BP antigen INSERM U519, but recognized exclusively a 450-kDa epidermal polypeptide. 22 boulevard Gambetta, This antigen has been cloned and identified as plectin by the 76183 Rouen cedex, deduced amino acid sequences.4±6 We report a patient with France atypical BP whose sera reacted with 450-kDa plectin as well ²Service de Dermatologie, as the 230- and 180-kDa BP antigens. Centre Hospitalier de Valence, A 62-year-old Japanese woman presented with a vesicular 179 boulevard du MareÂchal Juin, eruption on the trunk and extremities. She had noticed itchy 26000 Valence, lesions on the breast for 1 month, which extended to the France trunk and extremities. The lesions were characterized by ³Service de Dermatologie VeÂneÂrologie, multiple small and tense vesicles surrounded by patchy HoÃpital Edouard Herriot, erythema (Fig. 1a). She also had small erosions on the 5 place Arsonval, mucous membranes. Nikolsky's sign was absent. A skin 69003 Lyon, biopsy from the vesicles revealed a subepidermal blister with France eosinophil infiltration (Fig. 2a). Laboratory examination E-mail: [email protected] revealed leucocytosis (11´0 109 L21) and eosinophilia  (30%). These clinical and immunohistochemical features suggested a diagnosis of BP with vesicular lesions. She References received treatment with systemic prednisolone 60 mg daily for 10 days, which cleared the vesicular lesions and 1 Anhalt GJ, Kim S, Stanley JR et al. Paraneoplastic pemphigus. erythema. The prednisolone dose was gradually reduced to An autoimmune mucocutaneous disease associated with neoplasia. 15 mg daily. Five months later, she revisited our hospital for N Engl J Med 1990; 323: 1729±35. recurrent skin lesions. The new skin lesions were large, tense 2 Joly P, Thomine E, Gilbert D et al. Overlapping distribution of bullae on the trunk and extremities (Fig. 1b). Increasing autoantibodies specificities in paraneoplastic pemphigus and pemphigus vulgaris. J Invest Dermatol 1994; 103: 65±72. prednisolone to 40 mg daily resulted in improvement of the 3 Amagai M, Nishikawa T, Nousari HC et al. Antibodies against skin lesions, which enabled reduction of prednisolone to desmoglein 3 (pemphigus vulgaris antigen) are present in sera 20 mg daily. Despite extensive examination including blood from patients with paraneoplastic pemphigus and cause analyses and computed tomographic scans, a malignant acantholysis in vivo in neonatal mice. J Clin Invest 1998; 102: neoplasm or lymphoproliferative disorder was not found. 775±82. Direct immunofluorescence microscopy clearly showed linear q 2000 British Association of Dermatologists, British Journal of Dermatology, 142, 812±851 814 CORRESPONDENCE Figure 3. Western blots of epidermal cell extracts. Epidermal extracts were reacted with serum from a typical bullous pemphigoid patient (lane 1), antiplectin antiserum (lane 2) and the serum of the present patient obtained before treatment (lane 3) and at the recurrent stage (lane 4). Figure 1. Clinical appearance of the lesions. (a) Small and tense vesicles on the breast prior to treatment, and (b) large bullae on the arm after recurrence. Figure 2. (a) Histology of a vesicle on the breast (haematoxylin and eosin; original magnification 160). (b) Salt-split skin test  on lesional skin with the patient's serum obtained prior to treatment (original magnification 160).  q 2000 British