Bullous pemphigoid as a diagnostic and therapeutic challenge with a wide spectrum of dermatological symptoms

Introduction

Bullous pemphigoid (BP) is considered the most common autoimmune blistering dermatosis in Europe and in the USA. It is a chronic inflammatory skin disease that affects between 190–300 individuals per million annually [1]. It occurs more frequently in men than in women, predominantly in individuals over 80 years old. This dermatosis is characterized by the presence of well-tense blisters in the area of erythematous-oedematous eruptions, as well as in unaffected skin [2]. In some patients, the lesions may also appear on mucous membranes (20% of cases) [3]. Untreated BP can persist for months or years, with periods of remission and exacerbation. Although this dermatosis typically manifests on the skin, in our case, we present a patient in whom the disease primarily manifests in the oral cavity (on the soft and hard palate). Diagnosis is based on histopathological examination of a biopsy from the lesion. Therapy usually begins with local treatment using glucocorticosteroids (GCS), optimally with clobetasol, as the efficacy of other topical GCS has not been proven [4]. Second-line treatment involves systemic GCS therapy, immunosuppressants usually for the long-term [4].

Case report

A 74-year-old woman presented to the dentist with painful, irregular, non-healing ulcers covered with desquamating epithelium on the hard palate (fig. 1 A) and tense blisters and erosions located on the elbow (fig. 1 B). The patient did not report any systemic symptoms. Her medical history included comorbid schizophrenia, stress urinary incontinence, irritable bowel syndrome (IBS), and stable chronic ischemic heart disease. Symptomatic treatment was initiated with an antibiotic and local GCS in the form of a cream containing clobetasol, which provided temporary improvement. A biopsy from the involved hard palate before treatment revealed nonspecific granulation tissue with accompanying purulent inflammatory infiltrate. The findings were not diagnostic. After several months of symptomatic treatment, new, numerous lesions with blisters and erosions appeared, affecting the soft and hard palate as well as the mucous membrane of the right cheek. There were suspicious of being related to drug or reactive to systemic diseases that patient had. Due to primary hypertension, the patient was being treated with an angiotensin-converting enzyme inhibitor, which was considered a possible triggering factor. However, even after switching to a dihydropyridine derivative, the oral lesions did not resolve. A subsequent biopsy with direct immunofluorescence confirmed a definitive diagnosis of BP, revealing IgG deposits (+++), IgA deposits (+++), and C3 complement component deposits (+++) at the basement membrane zone (BMZ). Antibodies against basement membrane antigens were also positive in the IgA and IgG classes. After 1.5 years from the onset of the initial symptoms, new blisters appeared on the upper extremities, accompanied by erosions and erythematous changes on the extensor surface of the left forearm, accompanied by itching (fig. 1 B). Laryngological examination revealed blistering lesions in the area of the epiglottic folds. Finally, the lesions also involved the vulva. Therefore, systemic GCS therapy was initiated while continuing topical treatment, achieving complete remission of the disease.
Series of differential tests employed in diagnosis revealed only leukopenia (WBC 3.5 × 10³/μl). Multiple bacteriological and mycological swabs from the oral cavity yielded negative results. Tests for HBS antigen, anti-HCV antibodies, and HIV Ag/Ab (Combo) also yielded negative results. In order to exclude paraneoplastic syndrome, oncological diagnostics was conducted. Diagnostic tests for other autoimmune diseases were negative: normal proteinogram, negative ANCA, normal levels of complement components C3 and C4, negative RF, and negative inflammatory markers. Indirect immunofluorescence detected the presence of anti-nuclear antibodies (ANA) with a speckled and cytoplasmic staining pattern at a titre of 1 : 160. Euroline ANA Profile 3 did not detect the presence of specific antibodies against nRNP, Sm, SS-A, Ro-52, SS-B, Scl-70, PM-Scl, Jo-1, centromere B, PCNA, dsDNA, nucleosomes, histones, ribosomal P protein, or AMA-M2. The tested serum showed the presence of antibodies against BMZ antigens in the IgA class at a titre of 1 : 40 (positive IgA anti-pemphigoid antibody) and antibodies against BMZ antigens in the IgG class at a titre of 1 : 80 (positive IgG anti-pemphigoid antibody). The tested serum did not contain antibodies against pemphigus (negative IgG anti-pemphigus [desmoglein 1 and 3] antibodies, negative IgA anti-pemphigus antibodies).
Similar clinical and histological features are present in linear IgA bullous dermatosis (LABD), erythema multiforme, pemphigus vulgaris and foliaceus, and dermatitis herpetiformis (Duhring’s disease). Histopathological examinations and specific antibody testing allowed final diagnosis. ANA panel, ANCA, complement components C3 and C4, RF, CRP, and ESR ruled out connective tissue diseases of autoimmune origin or overlap syndromes. Switching from an angiotensin-converting enzyme inhibitor (ramipril) to a calcium channel blocker (lercanidipine) ruled out the possible drug related cause. Bullous diseases may precede or accompany squamous cell carcinomas [5]. Therefore, diagnostic tests were conducted in this regard. Imaging studies including chest X-ray and abdominal ultrasound, colonoscopy, gynaecological evaluation, faecal occult blood test, as well as tumour markers CA 15-3, CA 19-9, CA 125, CA 72-4, CYFRA 21-1, AFP, and CEA ruled out paraneoplastic syndrome. Due to the planned long-term corticosteroid treatment, a screening for osteoporosis, diabetes, and cataract monitoring was performed.
Before reaching the final diagnosis, the patient was receiving symptomatic antibiotics and topical treatments (rinses with hydrocortisone, vitamin B₁₂, nystatin). The result was partial and temporary achieved. Only the addition of a regular application of clobetasol cream provided consistent local improvement. This treatment was continued after confirming the diagnosis of pemphigoid. Methylprednisolone was introduced at a dose of 16 mg/day following the onset of skin and vulvar lesions, and the dose was reduced to 4 mg/day after the lesions subsided. During remission, the patient took 4 mg of methylprednisolone on even days and 2 mg on odd days. Due to chronic conditions, she was also taking haloperidol (for schizophrenia), trimetazidine (for ischemic heart disease), and tolterodine (for urinary incontinence). These medications could not be modified.

Discussion

A paucisymptomatic form limited to mucous membranes in BP can be challenging to diagnose, thus requiring precise differential diagnosis. Only the histopathological image and the presence of specific antibodies confirm the diagnosis. Despite three histopathological examinations of our patient, the diagnosis was ultimately confirmed through immunohistochemical testing. Serological diagnosis of BP is based on the enzyme-linked immunosorbent assay (ELISA), which detects circulating antibodies directed against the NC16a domain of the BP180 antigen and the BP230 antigen, with a sensitivity of 84% and a specificity of 90% [4]. However, false-positive results in ELISA testing can occur. This can be seen in patients with rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis [6]. False-positive results in ELISA testing also occur in elderly patients with itching [7]. Some argue that there is a correlation between the occurrence of false-positive results and a very low cutoff value [7]. Despite the high sensitivity and specificity of the ELISA test, there is a risk of obtaining a false-positive result due to a low level of autoantibodies against BP180 in the tested serum [7]. Therefore, during the diagnostic process for BP, the ELISA test should be used as one of the examinations but not as the sole determinant of diagnosis. Throughout the diagnostic process, the patient’s clinical presentation should be considered, and specific antibodies should be determined using recommended techniques such as ELISA, direct immunofluorescence (DIF), and indirect immunofluorescence (IIF) which were performed in our case. DIF revealed IgG, IgA and complement deposits bound at BMZ [7]. More recent technologies, such as BIOCHIP, are also being used for this purpose, providing high sensitivity and specificity to support the diagnostic process [8].
A specific feature of BP is the occurrence of lesions induced by physical factors (such as trauma, surgical procedures, thermal burns) [9]. In our patient, blisters appeared under a forearm cast. The patient experienced a scalding water burn, after which blisters developed that did not resolve despite wound healing, but improved only after GCS treatment was initiated. It is noticed that physical trauma induced BP typically occur in younger individuals, especially females. The lesions may develop at the site of exposure (e.g., burn), which generally heal well and do not tend to recur, or they may appear in other areas [9]. The initial symptoms of the disease usually manifest within a year, although they can occur even several years after exposure to the physical factor [9]. Immediately before the appearance of lesions on the forearm, the patient underwent cataract surgery, which may have contributed to disease exacerbation and new lesions formation. Drug-induced bullous disorders can be caused by antibiotics, β-blockers, angiotensin-converting enzyme (ACE) inhibitors, and neuroleptics (such as haloperidol, risperidone, biperiden) [9]. The more medications patients take, the more difficult it is to determine that one triggering BP [9]. BP can also be triggered by vaccination (e.g., influenza, tetanus), infections, and in association with haematological malignancies, renal or laryngeal cancer [9]. It has been observed that individuals with multiple sclerosis, schizophrenia, dementia, stroke, delusional disorders, personality disorders, and Parkinson’s disease may exhibit BP symptoms [10]. The risk of developing BP is three times higher in patients with dementia and Parkinson’s disease, and twice as high in patients with a history of stroke or epilepsy [9]. Our patient has schizophrenia, and her treatment may have been a triggering factor. Studies have shown that individuals with schizophrenia have an almost 50% higher frequency of autoimmune disorders [11, 12]. Another study revealed a significant association between BP and schizophrenia, with the highest increase in the risk of developing BP observed among older Jewish women with mental disorders [13]. Therefore, it is worth conducting psychiatric evaluations in patients with BP [13]. The occurrence of drug-induced BP is more characteristic in younger individuals [14]. Such a diagnosis should be approached cautiously in elderly patients.

Conclusions

BP has a characteristic clinical presentation, but sometimes repeated biopsies and immunopathological tests are needed to verify the diagnosis. A combination of antibody lab results, biopsy results, and clinical presentation remains the best method to confirm the diagnosis. Treatment for BP typically begins with topical corticosteroids, ideally clobetasol, as the effectiveness of other topical corticosteroids has not been proven [4, 15]. However, there is no commercially available registered product for mucous membranes in the Polish market, so in clinical practice, we use a compounded preparation. After achieving improvement in the patient, dexamethasone and fluocinolone were used. Although dexamethasone is not the preferred medication in the therapeutic management of BP, it proved to be effective. Our observations confirmed the efficacy of other topical corticosteroids, making dexamethasone and fluocinolone simpler and more readily available alternatives in polish conditions.

Funding

No external funding.

Ethical approval

Not applicable.

Conflict of interest

The authors declare no conflict of interest.

References