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Is dyshidrosiform pemphigoid really anti-p200 pemphigoid?

DII small banner By Warren R. Heymann, MD
Aug. 20, 2016

Dyshidrosiform pemphigoid (DP) was initially reported in a 72 year-old man with large, tense bullae on the plantar aspect of his feet, with some lesions on an erythematous base. He also had an “ill-defined papular eruption” of the trunk and an erosion of the posterior pharynx. Routine microscopy demonstrated a subepidermal bulla with “eosinophils and small round cells;” direct immunofluorescence revealed linear IgG and complement along the basement membrane zone; and indirect immunofluorescence, utilizing a monkey lip substrate, was positive with a 1:40 titer. The patient responded initially to a course of erythromycin and an intramuscular injection of 40 mg triamcinolone acetonide; further flares were ultimately controlled by dapsone. The entire condition resolved within 4 months.

In their discussion Levine et al asked: “Why should BP [bullous pemphigoid] develop only in localized areas?” They proposed that this could have occurred because of an antibody specific for antigens only in the skin of the feet, or by antigens “uncovered” only in the feet, or perhaps an absence of these antigens elsewhere in the skin (1).
Since the initial description of DP, more than 20 cases have been reported. While mostly noted in the elderly, there have been reports in younger patients, including a 20 year-old man with dapsone-responsive disease, who was found to have a positive ELISA for the BP180 antigen (2).

Meijer et al identified 12 patients with anti-p200 pemphigoid (7 male and 5 female; mean age, 66.6 years) using indirect immunofluorescence microscopy knockout analysis. Patients responded to typical pemphigoid treatments, although 75% required systemic therapy (mostly prednisolone). Histologically, most were neutrophil predominant, although eosinophils were noted (with neutrophils) in 5 cases. Direct immunofluorescence microscopy showed a linear n-serrated IgG deposition pattern along the basement membrane zone in 9 of 11 patients. The diagnosis was confirmed by immunoblot showing autoantibodies against 200-kDa protein in dermal extract in 12 of 12 patients. Autoantibodies against recombinant laminin γ1 were detected by immunoblot in 8 of 12 patients. Remarkable similarities were seen in clinical features with predominantly tense blisters on hands and feet, resembling dyshidrosiform pemphigoid. Mucosal involvement was seen in 6 (50%) of the patients. They concluded: “Predominance of blisters on the hands and feet may be a clinical clue to the diagnosis of anti-p200 pemphigoid”(3).

The authors acknowledge that their techniques of knocking out collagen VII of epidermolysis bullosa acquisita (EBA)and laminin 332 mucosal pemphigoid may not be readily available. The importance of differentiating both of these disorders is necessary, because of recalcitrance to therapy in the former, and risk of associated malignancy in the latter.

As most laboratories may not be equipped to definitively diagnose anti-p200 pemphigoid, the authors suggest that the DIF serration pattern analysis be performed, at least to easily rule out EBA. Perhaps I have not been reading the details of the DIF reports that I have been receiving lately, but I have never heard of this technique before. If you have a moment to look at reference 4 (with several of the same authors from reference 3), you will be able to see why they state that differentiating disorders the n-serrated pattern on salt-split skin (bullous pemphigoid, mucous membrane pemphigoid, cicatricial pemphigoid, linear IgA dermatosis, anti-laminin-332 pemphigoid and anti-p200 pemphigoid) versus the u-serrated pattern characteristic of EBA or bullous lupus is reasonably clear (4). Regardless, a definitive diagnosis of anti-p200 pemphigoid requires either immunoblot and/or knockout technology.

I raised a question in the title of this commentary — is DP really anti-p200 pemphigoid? Interestingly, in the caption of figure 1 (of Meijer et al), tense blisters and desquamation are displayed, “resembling dyshidrosiform pemphigoid.” Does that mean the authors think DP is distinct from anti-p200 pemphigoid? My hypothesis is that DP really is anti-p200 pemphigoid, and that Levine et al were correct in 1979 — it has just taken 37 years for newer immune-molecular techniques to define the specific antigen. The initial patient had the characteristic acral lesions with pharyngeal involvement. Although neutrophils were not mentioned in the biopsy report, the clinical response to dapsone suggests a neutrophilic component. The patient described by Lupi et al was positive for BP 180 antigen — that does not rule out concordant anti-p200 antibodies. While it would be wonderful (but virtually impossible) to retrieve the serum and tissue from the index case, any patient newly diagnosed with DP should be analyzed for anti-p200 BP, if possible. I also wonder what we will learn about other bizarre pemphigoid variants such as pemphigoid nodularis, pretibial pemphigoid, or pemphigoid vegetans.

1. Levine N, et al. Localized pemphigoid simulating dyshidrosiform dermatitis. Arch Dermatol 1979; 115: 320-1.
2. Lupi F, et al. Dyshidrosiform palmoplantar pemphigoid in a young man: response to dapsone. Acta Derm Venereol 2010; 90: 80-1.
3. Meijer JM, et al. Laboratory diagnosis and clinical profile of anti-p200 pemphigoid. JAMA Dermatol 2016; 152: 897-904.
4. Terra JB, et al. The n-vs. u-serration is a learnable criterion to differentiate pemphigoid from epidermolysis bullosa acquisita in direct immunofluorescence serration pattern analysis. Br J Dermatol 2013; 169: 100-5.

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