Exacerbation of Bullous Pemphigoid following a Closed Bone Fracture in an Elderly Patient: A Case Report

Abstract

Introduction

Bullous pemphigoid (BP) is the most common autoimmune blistering disorder affecting the elderly population. While the etiology is predominantly idiopathic, physical trauma has been identified as a potential exacerbating factor. Most trauma-induced cases reported in the literature are associated with surgical incisions, burns, or open wounds. The development of generalized BP following a closed fracture, where the skin integrity remains initially intact, is an exceptionally rare phenomenon. The patient experienced a pre-bullous phase starting in June 2025, which significantly progressed to generalized BP following a closed radius fracture in October 2025.

Case Report

We report the case of an 85-year-old woman who presented with a generalized blistering eruption 3 months after sustaining a closed fracture of the left radius. Physical examination revealed tense, fluid-filled bullae on an erythematous base involving the trunk and extremities. Histopathological analysis demonstrated a subepidermal blister with eosinophilic infiltration. The diagnosis was confirmed by direct immunofluorescence showing linear deposition of immunoglobulin G and C3 at the dermo-epidermal junction and enzyme-linked immunosorbent assay detecting high titers of anti-BP180 autoantibodies. The patient was treated with a tapering course of systemic prednisone, initiated at 90 mg/day. This regimen led to the cessation of new blister formation within 2 weeks and complete clinical remission with normalization of inflammatory markers within 3 weeks.

Conclusion

This case highlights that closed skeletal trauma, even without surgical intervention, can serve as a precipitating factor for generalized BP. The mechanism likely involves the release of sequestered antigens and epitope spreading due to internal tissue damage. Clinicians should maintain a high index of suspicion for BP in elderly patients presenting with cutaneous eruptions following orthopedic injuries to ensure prompt diagnosis and effective management.

Introduction

Bullous pemphigoid (BP) is the most prevalent autoimmune subepidermal blistering disease, primarily affecting the geriatric population [1]. The pathogenesis is characterized by the production of autoantibodies against hemidesmosomal proteins BP180 and BP230, leading to complement activation and subepidermal blister formation [2]. While many cases are idiopathic, various external triggers have been identified, including ultraviolet radiation, thermal burns, and certain medications like dipeptidyl peptidase-4 inhibitors [3].

Physical trauma has recently emerged as a significant localized or systemic inducer of BP. Most literature reports focus on surgical trauma, such as orthopedic arthroplasty or incision sites [4]. However, the development of generalized BP following a closed skeletal fracture – where the skin barrier remains initially intact – is a rare phenomenon that challenges our understanding of how internal tissue injury modulates systemic autoimmunity. In this report, we describe a case where a closed radius fracture acted as a potent exacerbating factor, accelerating the transition from a pre-bullous phase to generalized disease.

Case Report

An 85-year-old Kazakh woman presented to the clinic with generalized skin lesions. No other chronic diseases or allergic history was reported. Her medical history was notable only for mild hypertension, managed with enalapril for over 5 years. She had received no recent vaccinations. In June 2025, the patient developed pruritic maculopapular eruptions located on the abdomen, trunk, and both upper and lower extremities. She was initially treated with a diagnosis of allergic eczema. The initial pruritic maculopapular eruptions in June 2025 are compatible with the pre-bullous phase of BP, a well-recognized clinical entity in elderly patients often misdiagnosed as eczema.

In October 2025, the patient sustained a closed fracture of the left radius, which acted as a trigger, exacerbating the factoring factor involving stress, inflammation, and immune activation. In the subsequent months, October to December 2025, the pruritus intensified, and the lesions showed resistance to therapy. In January 2026, the disease progressed to a generalization stage. The rash spread extensively to the trunk and upper extremities, presenting a polymorphic picture characteristic of the advanced stage of pemphigoid. The patient’s medication history was reviewed; she had been on stable long-term therapy for enalapril for over 5 years. No new medications associated with drug-induced BP, such as DPP-4 inhibitors or NSAIDs, were introduced prior to the onset of symptoms.

Clinically, the patient presented with classic large, tense subepidermal blisters arising on an erythematous background, containing serous fluid. The lesions were generalized, extensively involving the abdomen, trunk, as well as both upper and lower extremities. Erosions and thick hemorrhagic crusts were observed at sites of healing (shown in Fig. 1).

Fig. 1.

The image shows a polymorphic eruption consisting of scattered tense bullae, numerous erosions, and thick hemorrhagic crusts on an erythematous background involving the trunk, abdomen, and both upper and lower extremities.

Taking into consideration the clinical features, diagnostic procedures were launched. Laboratory investigations revealed marked eosinophilia (17.9%; reference range <5%), elevated C-reactive protein (20.2 mg/L), and an erythrocyte sedimentation rate of 17 mm/h. A mild anemia was noted (hemoglobin 118 g/L), while the white blood cell count was 5.98 × 10⁹/L. Liver and kidney function tests were within normal limits for her age (creatinine 58 µmol/L, glucose 5.38 mmol/L, ALT 14.2 U/L, AST 21.4 U/L). Abdominal ultrasound examination disclosed diffuse changes in the liver and pancreas.

Diagnostic confirmation was achieved through immunofluorescence and serological assays. Direct immunofluorescence of perilesional skin revealed a linear band of immunoglobulin G (IgG) and C3 deposition along the dermo-epidermal junction. To distinguish from other blistering diseases, indirect immunofluorescence (IIF) on salt-split skin was performed, which found linear deposition of IgG localized on the epidermal side of the split, effectively excluding epidermolysis bullosa acquisita.

Further serological evaluation was conducted to identify specific target antigens. Enzyme-linked immunosorbent assay (ELISA) detected high titers of autoantibodies against BP180 (NC16A domain) and BP230 in the patient’s serum. Antibodies reactive with desmoglein 1 and 3 were not present. Histopathological examination confirmed a subepidermal split with an infiltrate rich in eosinophils. Crucially, there was no evidence of fibrinoid necrosis of vessel walls or leukocytoclasia, effectively ruling out cutaneous vasculitis.

Based on the clinical presentation of tense bullae, the subepidermal split on histology, the specific immunofluorescence pattern, and the presence of anti-BP180/BP230 antibodies by ELISA, the diagnosis of generalized BP was confirmed. Accordingly, systemic corticosteroid therapy was initiated. Prednisone was introduced at a starting dose of 90 mg/day (approx. 1.45 mg/kg). The dosage was subsequently tapered according to a 90–60–30 mg regimen over a 3-week period, leading to complete clinical remission.

Clinical Response: Following the administration of the systemic corticosteroid tapering regimen (prednisone 90–60–30 mg/day 3 weeks), the patient demonstrated a rapid and sustained therapeutic response. The formation of new bullae was ceased by the second week of treatment. By the eighth week, complete re-epithelialization of all cutaneous erosions was achieved. At the time of discharge, dermatological examination revealed no active blisters, erythema, or excoriations. The patient achieved full clinical remission.

Control laboratory investigations performed at the end of the 3-week course yielded normalization of key inflammatory parameters, correlating with the clinical improvement: Eosinophil decreased from a baseline of 17.9%–4.8%. C-reactive protein levels dropped from 20.2 mg/L to 4.3 mg/L. Hemoglobin levels improved from 118 g/L to 126 g/L, indicating resolution of the mild anemia associated with chronic inflammation.

Clinically, during the first week of therapy, the number of active blisters decreased significantly, replaced by hemorrhagic crusts and areas of pink re-epithelialized skin (shown in Fig. 2). By the third week, the crusts had detached, revealing smooth, residual pink skin with no new bullous lesions (shown in Fig. 3). Pruritus was significantly diminished, and the patient reported improved comfort.

Fig. 2.

Clinical response at week 1. Decrease in active blistering; formation of hemorrhagic crusts and early re-epithelialization at the sites of resolved bullae.

Fig. 3.

Clinical response at week 3. Complete detachment of crusts revealing smooth, pink epithelialized skin (post-inflammatory erythema); absence of new active blisters.

Discussion

The pathology of BP is fundamentally driven by an autoimmune attack on two specific hemidesmosomal proteins located at the dermal-epidermal junction, namely, type XVII collagen (COL17/BP180) and BP230 (dystonin). COL17 acts as a transmembrane protein spanning the lamina lucida and extending into the lamina densa. Its extracellular NC16A domain serves as the primary pathogenic epitope, with approximately 80%–90% of patient sera showing reactivity to this specific domain. Importantly, the levels of these antibodies correlate directly with disease activity, and their ability to cause subepidermal blistering has been confirmed experimentally through passive transfer models in neonatal mice [5].

In our case, the chronological relationship is distinct: a 4-month pre-bullous phase was followed by a fracture, which served as a catalyst, leading to full generalization within 3 months. This timeline clarifies that the fracture was not the primary cause but an aggravating factor. This aligns with the concept of “locus minoris resistentiae,” where tissue injury promotes the recruitment of inflammatory cells to a site where subclinical autoimmunity is already present.

In contrast, BP230 is an intracellular plakin protein found to be a target in 50%–80% of cases, specifically at its C-terminal domain. Unlike the well-established role of COL17, the pathogenicity of anti-BP230 antibodies remains a subject of debate as it is unclear whether they directly induce blistering or arise secondarily as a consequence of tissue damage [5]. The epitope spreading observed in our patient – indicated by high titers of both anti-BP180 and anti-BP230 – likely intensified following the fracture. Internal tissue disruption from the bone injury can release sequestered antigens, further fueling the autoimmune cascade in a patient already in a prodromal state.

A critical immunological feature of BP relevant to this case is epitope spreading, a phenomenon where the immune response broadens to target additional epitopes beyond the initial antigen. This process occurs in roughly 49% of patients and is typically associated with increased disease severity. Evidence from mouse models suggests a sequential progression mediated by CD40-CD40 ligand interactions wherein the immune attack usually begins against extracellular domains such as NC16A, spreads to the intracellular domains of COL17, and finally extends intermolecularly to BP230. However, the complexity of this mechanism is highlighted by the fact that the process is not strictly unidirectional. Rare clinical instances of reverse spreading have been documented where autoreactivity to BP230 develops prior to the emergence of antibodies against the NC16A domain of COL17 [5].

Several cases in the literature corroborate the link between orthopedic trauma and the onset of BP. For instance, a case involving a 61-year-old female described the development of generalized BP 1 month following the osteosynthesis of a femur fracture [6]. Similar to our patient, she had no history of skin disease or metal allergy. Her diagnosis was confirmed via ELISA (BP180 positive) and salt-split IIF. Interestingly, while her surgical wound healed within 2 weeks, the blistering eruption began at the scar site before generalizing. Remission was achieved after 15 months of methylprednisolone therapy.

The recurrent potential of trauma-induced BP was highlighted in a report of a 75-year-old man who developed generalized BP twice following total knee arthroplasty (TKA) [7]. In his first episode, BP appeared shortly after left TKA. Remarkably, 1 year later, following a right TKA, blisters reappeared as early as the second postoperative day. This case, confirmed by direct immunofluorescence (IgG, IgA, C3 deposits) and histopathology, underscores that surgical trauma can act as a potent re-activator of the autoimmune cascade.

Most relevant to our case is the report of localized BP following a closed wrist fracture in a 53-year-old woman [8]. Unlike the surgical cases, this patient had intact skin with no open wounds or implants, yet developed blisters exactly at the fracture site 1 month post-injury. Her diagnosis was confirmed by high levels of BP180 and BP230 autoantibodies.

A detailed comparison of the clinical characteristics between our case and previously reported trauma-induced BP cases is summarized in Table 1. The checklist of this case report was completed according to the CARE guidelines (online suppl. Material 1; for all online suppl. material, see https://doi.org/10.1159/000553401).

Table 1.

Comparative analysis of clinical and immunological characteristics of trauma-induced BP cases

Author	Sex	Age	Comorbidities	Exacerbation/clinical setting	Location of lesions	DIF findings	IIF/ELISA	Histopathology	Treatment	Outcome
Zeng R. et al. [6]	Female	61	Otherwise healthy; no history of metal allergy	Femur fracture surgery (titanium alloy plate)	Initially at the surgical scar, then generalized (limbs, trunk, face)	Clear band of IgG deposition at the dermo-epidermal junction	IIF: 1:20; salt-split IIF: IgG on epidermal side; ELISA: positive for BP180	Subepidermal vesicle with abundant eosinophil infiltrates	Methylprednisolone (1 mg/kg daily), tapered over 1 year	Healed; no relapse after 3 years
Kim Y.B. et al. [7]	Male	75	Hypertension and diabetes mellitus	TKA of left and right knees	First episode: buttocks, thighs, and operative site; second: buttocks	Strong positive IgG, with IgA and C3 at the basement membrane	Diagnosis confirmed by DIF and clinical presentation	Subepidermal blister with neutrophils and eosinophils	Prednisolone (10 mg twice daily)	1st episode: healed at 4 months; 2nd: resolved by 2.5 months
Ran D. et al. [8]	Female	53	Hypertension (on nifedipine)	Closed wrist fracture (intact skin, splint used)	Localized to the left wrist and back of the hand	Clear band of IgG and C3 at the dermo-epidermal junction	ELISA: BP180 (67.4 U/mL) and BP230 (>200 U/mL); salt-split: IgG on epidermal side	Subepidermal vesicles with abundant eosinophil infiltration	Oral minocycline (100 mg 2×/day) and nicotinamide (500 mg 3×/day)	Resolved in 2 months; no recurrence at 10-month follow-up

DIF, direct immunofluorescence; IIF, indirect immunofluorescence; ELISA, enzyme-linked immunosorbent assay; IgG, immunoglobulin G; IgA, immunoglobulin A; C3, complement component 3; TKA, total knee arthroplasty.

Our case shares critical features with these reports but presents a distinct clinical evolution. Similar to the 53-year-old patient with the wrist fracture, our 85-year-old patient sustained a closed fracture (radius) without surgical intervention. This supports the hypothesis that internal tissue disruption and inflammation alone – without external incision or metal implants – are sufficient to expose basement membrane antigens. However, unlike the wrist fracture case which remained localized, our patient developed a severe generalized form, similar to the postoperative femur and knee cases. The latency period in our case (3 months from fracture to full generalization, with a prodrome starting earlier) aligns with the variable timelines seen in literature, where symptoms typically manifest 1–3 months post-trauma. The presence of purpura and targetoid lesions in this case required a broad differential diagnosis. However, the diagnosis of BP was confirmed by the high titers of anti-BP180/BP230 ELISA and the characteristic ‘epidermal side’ staining on salt-split IIF, which, together with the absence of vasculitic changes on histology, excluded erythema multiforme and vasculitis.

In conclusion, this case illustrates that closed skeletal trauma can serve as a potent exacerbating factor for BP. It highlights the critical need to distinguish between the primary triggering of the disease and the secondary acceleration of a pre-existing pre-bullous-phase. Clinicians should closely monitor elderly patients with chronic pruritic dermatoses following orthopedic injuries as systemic stress and internal tissue damage may rapidly generalize localized autoimmune processes.

Statement of Ethics

Ethical review and approval were waived for this study in accordance with local legislation and institutional requirements as this is a retrospective case report describing clinical care and does not involve experimental interventions. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This study was not supported by any sponsor or funder.

Author Contributions

T.I. and Z.J. were involved in the diagnosis and clinical management of the patient. A.I.N. performed the literature search and drafted the manuscript. D.A., A.B., A.S., and T.I. analyzed the clinical data and contributed to the histological assessment. I.E.A. assisted with language editing and manuscript preparation. All authors critically reviewed the manuscript, approved the final version to be published, and agree to be accountable for all aspects of the work.

Funding Statement

This study was not supported by any sponsor or funder.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.