The Therapeutic Challenge in a Rare Case of Immunoglobulin A Type of Epidermolysis Bullosa Acquisita

Dear Editor,

Epidermolysis bullosa acquisita (EBA) is a rare autoimmune subepidermal blistering disorder that classically presents as vesicle and tense bullae over trauma-prone sites. It is broadly categorized as mechanobullous type, bullous pemphigoid type, linear IgA bullous disease (LABD) type, and mucous membrane pemphigoid type.[1,2] LABD has two subsets: classic LABD and IgA EBA (sublamina dense type of LABD). In classic LABD, the IgA antibodies bind to part of bullous pemphigoid antigen (120 KDa) with a roof pattern on a salt split, while in IgA EBA, these antibodies bind to type VII collagen with a floor pattern on the salt split.[1,2] We hereby present a rare subtype of IgA type of EBA which poses diagnostic and therapeutic challenges.

A 22-year-old woman presented with mild pruritic, multiple, erythematous, edematous plaques with clear fluid-filled tense blisters that ruptured to form raw areas over the trunk, forehead, and nape of the neck for the past 3 months. There was no history of photosensitivity, oral ulcers, recurrent fever, joint pain, or blisters at the site of trauma. Examination revealed multiple grouped clear to hemorrhagic fluid-filled vesicles, tense bullae, and hemorrhagic crusting with areas of healing in the form of hypopigmentation without scarring or milia formation. The rest of the mucosal, nail, and systemic examinations were normal [Figure 1]. Nikolsky sign and skin fragility tests were negative. Possibilities of LABD and bullous systemic lupus erythematosus (BSLE) were considered.

Figure 1.

Multiple grouped and discrete vesicles involving 5 to 6% body surface areas with clinical image depicting the face region

A skin biopsy of a vesicle revealed subepidermal cleavage with predominant neutrophilic infiltrates [Figure 2a]. Direct immunofluorescence showed a linear IgA (3+) and Ig G (2+) deposit at the basement membrane. Salt split indirect immunofluorescence demonstrated a floor pattern of IgA [Figure 2b] and IgG. Antinuclear antibody (ANA) and ANA profile were negative. The distinct clinical presentation of blisters in nontrauma sites, healing without scarring and milia formation, having both immunoglobulin deposits on DIF, and floor pattern on salt split led to the diagnosis of IgA EBA. The treatment administered is summarized in Table 1. Extensive search for malignancy yielded negative results. Serum IgA and IgG were normal. Partial remission was achieved despite combination therapy. She continued to develop 1-5 vesicles every day on the face, which were healing by themselves or with the application of topical mometasone cream, and the patient never attained lesion free period over the past 15 months [Figure 3]. The plan is to repeat the rituximab after 1 year and continue on maintenance doses of rituximab along with azathioprine.

Figure 2.

a: Histopathology demonstrating subepidermal split with predominant neutrophilic infiltrates [H and E, 100X] b: Salt split indirect immunofluorescence demonstrating floor pattern of IgA

Table 1.

Summary of drugs administered with response

Timeline	Drug	Duration	Response
March 2023	Tab Prednisolone 40 mg OD Tab Dapsone 100 mg OD	Dapsone was stopped after one month because of transaminitis (AST/ALT: 174/230 U/L) and anemia (Hb-8 g/dL)	Nil response (number of lesions 10-15 per day)
April 2023 to July 2023	Tab Prednisolone 40 mg OD Tab Doxycycline 100 mg OD	4 months	Nil response
August 2023 to September 2023	Tab Prednisolone 40 mg OD Tab Methotrexate 15 mg/week	2 months	Minimal response
October 2023 to December 2023	Tab Prednisolone 30 mg OD Tab Methotrexate 20 mg per week + Tab Apremilast 30 mg twice daily	3 months	Partial response (number of lesions 5-10 per day)
January 2024	Inj Rituximab 1 g 2 weeks apart + Tab Prednisolone 20 mg OD		Good response (number of lesions 2-3 per day)
March 2024	Tab Azathioprine 50 mg twice daily after rituximab + Tab Prednisolone 20 mg OD (Due to the continuous development of the vesicles on the face, methotrexate and apremilast were stopped and azathioprine was added)	4 months	Moderate response (5 lesions per day)
July 2024 (last visit)	Tab Prednisolone 10 mg OD Tab Azathioprine 50 mg BD		1-5 vesicles per day on the face only Self-healing/healing with topical mometasone cream

OD: Once daily, BD (bis in die): Twice daily, AST: Aspartate transaminase, ALT: Alanine transaminase, Hb: Hemoglobin, U/L: Units per liter, g/dL: gram per deciliter

Figure 3.

Clinical image depicts near complete response post therapy

IgA EBA is a less known and rare condition. The clinical presentation described in the literature includes erythematous to urticated papules, plaques, vesicles, and tense bullae.[2,3] Milia, scarring, and involvement of nails are not seen in this spectrum; hence, they are indistinguishable from other inflammatory vesiculobullous disorders. The lesions can be seen as localized, as in our case, or can be widespread. It is mostly located on the extremities, unlike our case (predominantly involves the face).[4] Apart from DIF, salt split technique, immunoelectron microscopy (IEM), and fluorescence overlay antigen mapping (FOAM) can be used to identify the target antigen for a specific type of blistering disease. In IEM and FOAM technique, the patient autoantibody binds to healthy skin while negative fluorescence in the skin of patients with a null mutation of collagen 7 genes.[5] Few studies showed 30% false negative for type VII collagen IgA antibodies, and enzyme-linked immunosorbent assay with recombinant type VII collagen has been used to identify IgG.[5] Positive IgA staining with or without IgG is mandatory to diagnose IgA EBA, while the presence of IgG will not make it inflammatory variant of EBA.[6] There are reports of deposition of both IgG and IgA with roof pattern on salt split known as linear IgA/IgG dermatosis. By contrast, our case has the deposition of both IgG and IgA with a floor pattern that distinguishes from the former and is mixed immunobullous dermatosis (consistent with EBA).[3] Our patient had both IgG and IgA deposits on DIF and floor pattern on salt split, which has been recognized as a controversial subset of IgA EBA.

Type VII collagen is an autoantigen in many autoimmune bullous dermatoses such as EBA, sublamina dense type of LABD, and BSLE.[7] EBA is delineated from BSLE clinical and immunological features (ANA positivity) of SLE. Case reports on the association of EBA with malignancies such as lymphoma, multiple myeloma, genitourinary malignancies, thyroid, and pancreatic carcinoma have been reported.[8] Thereby, a workup for both hematological and solid organ malignancy is required as there are reports of disease triggered by malignancies. However, in our case, a detailed evaluation did not reveal any malignancy.

To the best of our knowledge, there are few reports on mixed immunobullous dermatosis, especially of the EBA variant. Most of the patients are therapy-resistant and need complex combination therapies. Extensive evaluations are required to diagnose as higher immunosuppression is required for disease control.

In conclusion, our case underlines the challenges associated with diagnosing and managing IgA EBA, a rare variant without any skin fragility, scarring, milia formation, and nail involvement. In addition, multiple combination therapies, including rituximab, could not provide the patient with a disease-free period.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.