Long-lasting Localized Pemphigus Vulgaris without Detectable Serum Autoantibodies Against Desmoglein 3 and Desmoglein 1.

Pemphigus vulgaris (PV) is an autoimmune blistering disease elicited by anti-desmoglein (DsG) 3 antibody. Although skin lesions tend to be distributed over the entire body, in some patients, they are confined to a restricted area. We report two patients who presented with long-lasting localized PV without detectable anti-DsG antibodies after suffering antibody-positive systemic PV. Initial treatment with prednisolone (PSL) was successful in both patients, but a local relapse occurred on the cheek or lower lip after a reduction in the PSL dose. Biopsy of the localized lesions showed suprabasal acantholysis; no serum DsG antibodies were found. Local immunosuppression therapy was effective in both patients. Based on our findings, we suggest that localized PV without detectable antibodies can develop after systemic PV.

What was known?

Pemphigus vulgaris is an autoimmune systemic blistering disease elicited by desmoglein 3 antibody.

Introduction

Pemphigus vulgaris (PV) is a systemic autoimmune blistering disease that presents with flaccid intraepithelial blisters, erosions, and ulcerations of the skin and mucous membranes. Autoantibody against desmoglein (DsG) 3 was identified as the pathogenic antibody. The level of circulating antibody tends to correspond with the clinical severity of the disease which may remain limited to a single site over a long time. The term “localized PV” is used to describe such cases.[12345]

We report two patients with localized PV that appeared after their systemic PV responded to systemic corticosteroid therapy.

Case Reports

Case report 1

A 43-year-old female with a 2-year history of PV was referred to our hospital because of persistent erythema restricted to her left cheek. Widespread blisters and erosions were seen on her face, lips, buccal and nasal mucosa, trunk, and limbs and a diagnosis of PV was made. Her serum antibodies against DsG 1 and 3 were 57 and 810 units/ml, respectively. A skin biopsy from her buccal mucosa and right axilla revealed a suprabasal cleft with acantholytic keratinocytes. Direct immunofluorescence (DIF) study of the same region revealed intercellular deposits of immunoglobulin G (IgG) and C3 in the epidermis. A diagnosis of PV was made and oral prednisolone (PSL, 50 mg/day) was started. The eruptions improved quickly and her autoantibodies became negative. The PSL dose was gradually tapered. However, at a PSL dose of 22.5 mg/day, she suffered recurrent flare-ups of erythema on her left cheek for over a year [Figure 1a and b]. Skin culture was negative for any microbe. Anti-DsG 1 and 3 antibodies were negative for approximately 2 years, and indirect immunofluorescence (IIF) test was also negative 1 year after the relapse. Rebiopsy of the cheek showed suprabasal acantholysis and deposits of C3 and IgG by DIF [Figure 1c and d], whereas DIF from her unaffected skin was negative. We added topical tacrolimus (0.1%) ointment without changing the PSL dose because the PV lesion was localized. The eroded patch on her left cheek improved by day 7 and was almost completely epithelialized after 2 weeks [Figure 1e]. Treatment with tacrolimus ointment was continued and PSL was reduced to 15 mg and she suffered no relapse for 6 months.

Figure 1

(a) The erythema and the erosions were limited to the left cheek. (b) Close-up view of Figure 1a. (c) Lesional skin biopsy revealed suprabasal acantholysis. (d) Direct immunofluorescence showed intercellular immunoglobulin G deposits in the epidermis. (e) The lesion on the left cheek epithelialized almost completely

Case report 2

A 67-year-old female diagnosed with PV 5 years earlier had been successfully treated with oral PSL started at 60 mg daily. When the dose was tapered to 6 mg/day, erosions lasting for over a year appeared on her lower lip [Figure 2a]. Although the biopsy specimen showed suprabasal acantholysis [Figure 2b] and intercellular deposits of C3 and IgG by DIF, anti-DsG 1 and 3 antibodies were negative 1 year after the flare-up. The lesion responded to topical corticosteroid without changing the PSL dose.

Figure 2

(a) The erosions were limited to the lower lip. (b) Lesional skin biopsy revealed suprabasal acantholysis

Discussion

We experienced two cases of localized PV subsequent to systemic form. In both cases, antibodies against DsG-3 were positive in the systemic stage and negative when the localized form appeared.

Others[67] who reported patients with localized PV suggested that the lesions were confined to a limited area due to Koebner's phenomenon. One of our patients (Case 1) habitually wore a mask to prevent infection and the lesion arose at the edge of the mask. The detailed mechanism(s) underlying its appearance is (are) unknown.

In their experimental study, Egawa et al.[8] demonstrated that at the sites of inflammation, permeability of postcapillary venules was selectively induced and all subclasses of Ig (molecular size ranges from 146 to 990 kDa) were able to traverse the vascular endothelium. On the other hand, the traffic of plasma content larger than 70 kDa was restricted under homeostatic conditions. Positivity of the DIF test in the lesion and the negative test results in the unaffected skin of Case 1 coincide with their findings. We posit that when the autoantibody titer is high enough, pathogenic antibodies can translocate from serum to the skin under homeostatic conditions and at inflammatory sites and that blister formation is limited to the inflammatory sites with trace amounts of antibodies. According to Yagi et al.,[5] serum autoantibodies against DsG were undetectable and the IIF test was negative in some patients with localized PV. The absence or low titer of circulating autoantibodies may explain the development of localized lesions.[9]

Kamiya et al.[10] reported that very low serum levels of anti-DsG 3 that returned negative results on chemiluminescence enzyme immunoassay (CLEIA) could be detected by enzyme-linked immunosorbent assay (ELISA) using sera concentrated 10 times (highly sensitive ELISA). We assume that the level of anti-DsG antibodies was very low but not absent in our cases.

The systemic lesions of our patients responded well to oral PSL. We posit that the localized form of PV appeared when the autoantibodies became undetectable by conventional CLEIA. The localized lesions responded to topical tacrolimus without increasing the PSL dose.

Our experience suggests that physicians should be alert to localized PV that appears after amelioration of the systemic form and the marked decrease in pathogenic antibodies. Because of the low level of antibody, these lesions respond well to treatment with topical immunosuppressive agents.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

What is new?

Localized PV without detectable antibodies developed after amelioration of systemic form. These localized lesions responded well to topical immunosuppressive agents.