Case of Juvenile Bullous Pemphigoid with Negative Serum BP180 ELISA Test Reveals Need for Additional Testing

Researchers recently reported a case of a juvenile female with bullous pemphigoid (BP) and a negative BP180 ELISA test. Details of the case were published in Pediatric Dermatology.¹

These findings, they wrote, point to factors that may delay a BP diagnosis, ultimately hindering a patient's care.

Image Credit: © DermNet

Background and Methods

Enzyme-linked immunosorbent assay, or ELISA testing, detects specific antigens or antibodies in a sample using enzyme-linked reactions. Its applications in dermatology may include cytokine research and the diagnosis of infectious diseases, bullous dermatoses, vasculitis, and connective tissue disorders.²

BP in particular targets the BP180 protein. This complicates testing and diagnosis, as standard tests may miss atypical cases where antibodies target different BP180 regions.³ In cases of juvenile BP, which is rare in nature, a diagnosis may first require comprehensive testing due to its diagnostic challenges, according to authors of the present case study. This, they noted, may warrant use of ELISA testing versus standard tests such as histopathology, direct and indirect immunofluorescence studies, and salt-split skin tests.⁴

The case involved a 6-year-old girl was referred to a pediatric dermatology department with initial symptoms of itchy eruptions on her trunk and extremities, coupled with oral erosions. Clinicians first attempted intervention with topical clobetasol 0.05% and hydrocortisone 2.5% — neither of which had any significant clinical effect, and her symptoms persisted.

Findings

Following initial laboratory testing, clinicians began to consider bullous systemic lupus erythematosus (SLE) as a differential diagnosis, given an elevated antinuclear antibody titer and lymphopenia. Corresponding autoimmune panels used to aid in the diagnosis of bullous SLE were deemed normal with no antibodies substantially lower or higher that would be indicative of this condition. To further eliminate the possibility of bullous SLE, researchers observed the patient's lack of common clinical features, such as arthritis, photosensitivity, or malar rash.

However, clinicians also observed that her serum IgE was markedly elevated. Upon conducting a perilesional punch biopsy, they observed sub-epidermal blistering, as well as acute and chronic inflammation. Further testing also revealed a linear deposition of IgG and C3, with IgM, IgA, and fibrinogen being notably absent.

Researchers then made a diagnosis of neutrophilic subepidermal vesicular dermatosis and initiated combination therapy with 1 mg/kg of prednisone and 25 mg of dapsone daily for a duration of 4 months. However, upon tapering the dosage of prednisone over the course of 4 months, researchers observed skin and oral blister recurrence.

Follow-up was interrupted for approximately 2 years, after which the patient was secondarily evaluated at a blistering clinic. Clinicians recorded negative serum ELISAs for BP180 (NC16A), BP230, and collagen VII.

Additionally, further testing not only revealed negative ELISA results, but negative reactivity to collagen VII and laminin 332. However, an immunoblot analysis demonstrated reactivity to the NC16A and NC4 domains of BP180.

After lesion recurrence and the onset of active blistering, clinicians treated the patient with topical clobetasol 0.05%, hydrocortisone 2.5%, and tacrolimus 0.03%. Due to her history of esophageal lesions and logistical barriers, they initiated treatment with 375 mg/m² of rituximab on a schedule of 4 weekly doses, leading to esophageal lesion resolution and significant skin lesion improvement.

Conclusions

According to authors of the case report, this case represents the first time a juvenile case of BP accompanied by a negative serum BP180 ELISA test has been reported in the scientific literature.

"This report emphasizes that the CLIA-approved ELISA alone is not adequate to rule out pemphigoid and its variants," according to Fairley et al. "Physicians caring for these patients should know that a negative test is inadequate to exclude BP and that further workup (including IIF) is warranted."

Moving forward, they acknowledged that this case further emphasizes the need for a complete immunodiagnostic workup in patients with suspected BP. These workups, they noted, can result in more timely diagnosis and treatment, ultimately improving patient care.

References

1. Fairley JA, Berrebi KG, Poggemiller AM, Varzavand A, Messingham KN. Diagnostic challenge: juvenile bullous pemphigoid with a negative BP180 ELISA. Pediatr Dermatol. August 21, 2024. https://doi.org/10.1111/pde.15741
2. Yuil JMR, Pérez PM, De Ríos EY, Castro MR. ELISA and its applications in dermatology. Dermatología Cosmética Médica y Quirúrgica. July 2012. https://www.researchgate.net/publication/286587036_ELISA_and_its_applications_in_dermatology
3. Waisbourd-Zinman O, Ben-Amitai D, Cohen AD, et al. Bullous pemphigoid in infancy: clinical and epidemiologic characteristics. J Am Acad Dermatol. 2008; 58(1): 41-48.
4. Baigrie D, Nookala V. Bullous pemphigoid. StatPearls [Internet]. StatPearls Publishing. January 2024. Updated March 2, 2023. https://www.ncbi.nlm.nih.gov/books/NBK535374/