Abstract
Key Clinical Message
As dermatologists, we must be aware that even limited localized lesions may signal a life‐threatening condition, for which early diagnosis and treatment can improve the prognosis.
Abstract
Bullous pemphigoid is an autoimmune disorder characterized by blister formation. Hypereosinophilic syndrome is a myeloproliferative disorder featuring papules, nodules, urticarial lesions, and blisters. The coexistence of these disorders may highlight the involvement of common molecular and cellular factors. Here, we describe a 16‐year‐old patient with hypereosinophilic syndrome and bullous pemphigoid.
Keywords: bullous pemphigoid (BP), corticosteroids, hypereosinophilic syndrome (HES)
1. INTRODUCTION
Bullous pemphigoid (BP) is one of the most common blistering dermatoses, characterized by autoantibodies against hemidesmosomal proteins of the skin and mucosa. 1 Hypereosinophilic syndrome (HES) is a myeloproliferative disorder characterized by persistent hypereosinophilia, leading to possible organ damage with cutaneous or systemic manifestations. 2 Several cases of BP with coexisting HES have been reported in the literature. Peripheral eosinophilia, reported in both BP and HES, can indicate the severity of each disease and may play a role in the pathogenesis of these conditions. 3 Here, we describe a female patient initially diagnosed with BP. Following a lack of response to usual BP treatment and because of persistent eosinophilia, the diagnosis of idiopathic HES associated with BP was established.
2. CASE PRESENTATION
A 16‐year‐old female patient presented to our hospital with generalized bullous eruptions. Five years earlier, she had developed scattered bullae on the trunk, treated successfully with prednisolone 15 mg daily, which was tapered gradually. One year before, she was referred to our center due to repeated bullous lesions that did not respond to dapsone, intravenous immunoglobulin, rituximab, and even the previous dose of prednisolone. During the current episode of illness, she was referred to our hospital with generalized bullae. Her physical examination showed multiple tense bullae on the lower and upper extremities, trunk (Figure 1), and neck, in addition to oral lesions. Skin biopsy and the histological evaluation showed subepidermal blisters with eosinophilic perivascular infiltrates (Figure 2). Direct immunofluorescence (DIF) showed linear C3 deposits at the level of the dermo‐epidermal junction, with circulating IgG autoantibodies binding to the epidermal side salt‐split skin. These antibodies reacted with BP180NC16A by Western blotting. Laboratory findings included hypereosinophilia (peripheral smear eosinophils: 44%; absolute eosinophil count: 1600/μL). According to an internal medicine consult, bone marrow biopsy and aspiration were performed. The results revealed a hypercellular bone marrow with 75% eosinophils and blasts. The final diagnosis was BP associated with HES. Genetic testing for the FIP1L1‐PDGFRA fusion gene was negative. Hence, high dose prednisolone (40 mg/day) was initiated. There was a complete resolution of her skin lesions. Later, prednisolone was tapered gradually.
FIGURE 1.
Multiple tense and flaccid bullae on the trunk, abdomen, back, and upper extremities, in addition to erosions.
FIGURE 2.
A subepidermal blister containing eosinophils and fibrin.
3. DISCUSSION
The skin is the most frequent organ involved in HES, affecting more than half the patients through urticarial lesions, pruritic papules or nodules, or mucosal ulcers. 4 Histopathological studies of papular or nodular lesions usually show abundant eosinophilic perivascular infiltrates in addition to neutrophilic and mononuclear ones, whereas mucosal ulcers histology includes nonspecific mixed cellular infiltrates with no vasculitis. 4
Bullous pemphigoid is a blistering autoimmune disease that predominantly affects older adults. 5 Histopathological studies show subepidermal blister formation rich with eosinophils, whereas direct or indirect immunofluorescence assays demonstrate the presence of IgG and/or C3 deposition along the basement membrane zone. 5 The cornerstone of treatment is corticosteroids; other options include doxycycline, dapsone, and immunosuppressants (5). Recent studies showed the role of eosinophils and IgE autoantibodies, in addition to anti‐BP180 and BP230 IgG autoantibodies, in the pathogenesis of BP. 6
Hypereosinophilic syndrome (HES) is a heterogeneous entity characterized by eosinophilic infiltrates, especially in the bone marrow and heart, followed by the lungs, liver, and spleen (7). One of HES cutaneous manifestations is blister formation, usually in the epidermis or dermal‐epidermal junction, making it a differential diagnosis of BP (7). We were able to find seven cases of BP with coexisting HES (Table 1). The coexistence of these two disorders may highlight similar molecular and cellular backgrounds. 7
TABLE 1.
Review of literature on bullous pemphigoid cases associated with hypereosinophilic syndrome.
| Author/Year | Sex /Age (years) | Country | Lesion location | Physical examination | FIP1L1‐ PDGFRA gene | Treatment |
|---|---|---|---|---|---|---|
|
Palleschi et al/1996 |
Male/77 | Italy | Trunk/Limbs |
Erythematous papules |
Unknown |
Corticosteroid |
|
Belgnaoui et al /2002 |
Male/58 | France | Generalized | Pruriginous bullous dermatosis | Unknown |
Corticosteroid |
| Muller et al/2006 | Male/70 | Germany | Unknown | Pruriginous, bullous pemphigoid‐ like lesions | Negative |
First: Corticosteroid + Azathioprine then Imatinib |
| Felbert et al/2006 | Female/74 | Germany | Generalized | Prurigo‐like lesions | Unknown | First:Corticosteroid, Azathioprine and Doxycyline; then: Mycophenolate mofetil |
| Hofmann et al/2007 | Male/70 | Germany | Feet, buttock, leg |
Tense bullae, erythematous papules, excoriation |
Negative |
Corticosteroid, Imatinib |
| Hassam et al/2010 | Female/31 | Morocco | Generalized |
Bullous eruption |
Negative |
Corticosteroid, Interferon‐alfa and Hydroxyurea |
| Maniyan et al/2019 | Female/55 | India |
Forearms, Legs, Trunk, Face |
Pruritic papules, vesicles, tense bullae | Unknown |
Corticosteroid, Dapsone, Diethylcarbamazine, Hydroxyurea |
| The present case | Female/16 | Iran | Generalized | Tense bullae | Negative | First: Dapsone, IVIG, Rituximab; then: Corticosteroid |
Treatment of HES is based on the presence or absence of the FIP1L1‐PDGFRA fusion gene. When the genetic test is positive, the best treatment is imatinib, whereas when the test is negative, corticosteroids represent the the first line of treatment. 8
This case report underscores the critical role of dermatologists in diagnosing every skin manifestation, even when cutaneous lesions are limited, because a life‐threatening condition may exist. 9 BP is a common blistering disorder that may be associated with HES. 9 HES must be considered in patients with atypical corticosteroids response and eosinophilia. 9 Our patient presented first with limited bullous lesions that resolved with corticosteroid treatment, but later recurred with a more generalized aggressive course with no response to low‐dose corticosteroids. After identifying the concomitant HES and commencing prednisolone at the treatment dose for HES (1 mg/kg/day), there was a complete resolution of the skin manifestations.
In 2020, Farnaghi et al. examined the correlation between BP clinical severity and dermal and peripheral blood eosinophilia, anti‐BP‐180, and anti‐BP‐230 IgG.
Anti‐BP‐180 and anti‐BP‐230 levels, the severity of tissue inflammation, and dermal eosinophilia strongly correlated with the severity of BP. Hence, the severity of tissue inflammation and eosinophil infiltration may indicate BP severity and prognosis. 10
In our patient, prednisolone, dapsone, IVIG, and rituximab were all tried, but there was a persistent elevation in eosinophil count. This finding was later confirmed by bone marrow aspiration, which showed a hypercellular bone marrow with 75% eosinophils and blasts and confirmed our final diagnosis: BP associated with HES.
This report underlines the importance of skin manifestations in that even limited localized lesions may signal a life‐threatening condition, where early diagnosis and treatment can improve the prognosis. 11
AUTHOR CONTRIBUTIONS
Raziyeh Ganji: Conceptualization; writing – original draft. Reem Diab: Investigation; writing – original draft; writing – review and editing. Farideh Moussavi: Visualization; writing – original draft. Fahimeh Abdollahimajd: Supervision; validation; visualization; writing – original draft; writing – review and editing.
FUNDING INFORMATION
This research did not receive any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors.
CONFLICTS OF INTERESTS STATEMENT
The authors have no conflicts of interest to declare.
CONSENT
Written informed consent was obtained from the patient's family for the publication of this case report and any accompanying images.
Ganji R, Diab R, Mousavi F, Abdollahimajd F. Recalcitrant course of bullous pemphigoid indicating coexisting hypereosinophilic syndrome: A case report and literature review. Clin Case Rep. 2023;11:e7384. doi: 10.1002/ccr3.7384
Raziyeh Ganji and Reem Diab the first two authors are contributed equally.
DATA AVAILABILITY STATEMENT
Not applicable.
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Data Availability Statement
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