Kaposi sarcoma following dupilumab treatment for bullous pemphigoid: A case report and review of literature

Abstract

BACKGROUND

Dupilumab has shown therapeutic efficacy in bullous pemphigoid (BP) by blocking interleukin (IL)-4/IL-13 signaling; inducing a type 22 immune signature with increased AHR signaling, keratinocyte activation and IL-22 receptor upregulation; and indirectly regulating STAT3 pathway activity to reduce the need for systemic immunosuppressants and glucocorticoids. The pathogenesis of Kaposi sarcoma (KS), a rare BP complication, is closely associated with human herpesvirus-8 and the STAT3 pathway.

CASE SUMMARY

An 87-year-old female was diagnosed with BP based on clinical, histopathological, and immunological findings. Good control was achieved with low-dose oral prednisone, dupilumab, and topical halometasone-triclosan cream. After 32 weeks of treatment, she developed violaceous-red papules on both feet, which were confirmed as KS by skin biopsy and immunohistochemistry. Human immunodeficiency virus, syphilis, systemic disease, and internal malignancy were excluded. The patient declined laser/cryotherapy for KS due to advanced age and poor mobility, and was treated with topical 5% imiquimod cream. At the 6-month follow-up, no new KS lesions occurred, with partial regression of existing lesions. BP remained well controlled under regular surveillance.

CONCLUSION

Further research and follow-up are needed to clarify BP-KS association and dupilumab’s safety.

Key Words: Bullous pemphigoid; Dupilumab; Kaposi’s sarcoma; Interleukin-6/TYK2/STAT3; Kaposi sarcoma-associated herpesvirus; Herpesvirus 8; Immune evasion; Case report

Core Tip: Dupilumab was used to treat bullous pemphigoid (BP) complicated with Kaposi sarcoma (KS). The causes were analyzed, and the immune drift induction hypothesis was proposed. STAT3 plays a key role in KS pathogenesis, as it supports human herpesvirus-8 latency and viral replication. It can be activated by virally encoded interleukin-6 via gp130 receptor signaling to promote the survival and proliferation of infected cells. Dupilumab-induced immune deviation (toward Th1/Th17/Th22 pathways) and STAT3 signaling activation may contribute to KS occurrence in susceptible BP patients. Further investigation is needed.

INTRODUCTION

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease that predominantly affects elderly individuals and can significantly impair quality of life. Despite the availability of multiple therapeutic options, disease management remains challenging[1,2]. The detection of autoantibodies against basement membrane zone components, particularly BP180 and BP230, is diagnostically significant[3]. Antibodies targeting basement membrane zone components may include not only immunoglobulin G but also immunoglobulin E, which may contribute to BP pathogenesis[4]. Type 2 immune responses are considered key drivers in the development and progression of BP[5].

Dupilumab, a monoclonal antibody targeting interleukin (IL)-4 receptor alpha, blocks IL-4 and IL-13 signaling and has shown promise in the treatment of BP[5-7]. By suppressing type 2 inflammation, dupilumab may reduce the need for systemic corticosteroids and other immunosuppressive agents. This could lower the risk of treatment-related adverse events in elderly patients.

Kaposi sarcoma (KS) is a rare vascular endothelial tumor associated with human herpesvirus-8 (HHV-8) infection. Its incidence increases in immunocompromised individuals, including those receiving immunosuppressive therapy for autoimmune blistering diseases[8]. Here, we report a case of KS developing several months after initiating dupilumab therapy in a patient with confirmed BP and discuss the possible clinical association.

CASE PRESENTATION

Chief complaints

An 87-year-old woman complained of widespread vesicles and bullae for 9 months, and multiple tender erythematous papules on both feet for 32 weeks.

History of present illness

After 32 weeks of combination treatment with prednisone and dupilumab, the patient developed multiple tender erythematous papules on both feet.

History of past illness

She denied any previous history of infectious diseases or malignancy.

Personal and family history

No relevant personal or family history was documented.

Physical examination

Physical examination revealed multiple tense vesicles and bullae on the trunk and extremities, with thickened walls and a negative Nikolsky sign. There were > 10 discrete, hemispherical, violaceous-red papules on both feet (Figure 1). There were no signs of stasis dermatitis or varicose changes in the lower extremities.

Figure 1 Clinical presentation of Kaposi sarcoma lesions after 32 weeks of treatment. A-C: Multiple violaceous-red papules on both feet after 32 weeks of treatment.

Laboratory examinations

Laboratory testing was negative for human immunodeficiency virus (HIV) and syphilis (Treponema pallidum particle agglutination assay/toluidine red unheated serum test), and routine laboratory parameters were within normal limits. Skin biopsy obtained from a fresh blister on the trunk demonstrated subepidermal blister formation with eosinophilic infiltration, consistent with BP. Punch biopsy obtained from a papule on the right heel revealed vascular proliferation suggestive of KS (Figure 2). Immunohistochemical analysis showed tumor cells positive for erythroblast transformation specific related gene, CD31, CD34, HHV-8 (partial), D2-40, and Ki-67 (60%+) (Figure 3).

Figure 2 Histopathological features of Kaposi sarcoma (hematoxylin and eosin staining, × 200). Slit-like vascular spaces containing extravasated erythrocytes are observed, surrounded by proliferating spindle cells, consistent with the characteristic pathological features of Kaposi sarcoma.

Figure 3 Immunohistochemical staining of Kaposi sarcoma lesions (× 200). A-F: Representative immunohistochemical staining demonstrating tumor cell markers in Kaposi sarcoma tissue. Tumor cells were positive for ERG (A), CD31 (B), CD34 (C), human herpesvirus-8 (partial positive) (D), D2-40 (E), and Ki67 (approximately 60% positive) (F).

Imaging examinations

Whole-body computed tomography and gastrointestinal endoscopy showed no evidence of systemic abnormalities or malignancy. Dermoscopic examination of the lesions on both feet demonstrated purplish–red lacunar structures.

FINAL DIAGNOSIS

A final diagnosis of BP with KS was established.

TREATMENT

Initial treatment for BP was oral prednisone (initial dose 15 mg/day for 2 weeks, followed by gradual tapering to 5 mg/day and then reduced to 2.5 mg every other day after 24 weeks as maintenance therapy) in combination with dupilumab (loading dose 600 mg administered subcutaneously, followed by 300 mg every 2 weeks). Halometasone-triclosan cream was applied topically to affected areas.

The patient developed multiple tender erythematous papules on both feet. After 32 weeks of treatment, BP remains well controlled with low-dose prednisone (2.5 mg every other day) and dupilumab (300 mg every 2 weeks). For the KS lesions on the feet, carbon dioxide laser therapy or cryotherapy was recommended; however, these options were declined by the patient’s family due to the patient’s advanced age and limited mobility. Instead, topical 5% imiquimod cream was initiated.

OUTCOME AND FOLLOW-UP

At the 6-month follow-up visit, BP was stable, with almost no new blisters. Regarding KS, the patient experienced local erythema and pruritus during imiquimod use, which was tolerable. At the latest follow-up, no new foot lesions were observed. The smaller rashes had basically resolved, and the larger ones had decreased in size. The patient remains under regular clinical observation.

DISCUSSION

BP is an autoimmune subepidermal blistering disorder that primarily affects elderly individuals and is characterized clinically by tense blisters on normal or erythematous skin[1]. BP is associated with a range of complications[9,10] and may become life-threatening in severe cases, highlighting the need for careful and individualized management. A review of previously reported BP-associated complications identified several cases of KS occurring in patients with BP, providing a relevant clinical context for this case report.

KS is a rare multifocal vascular tumor caused by KS-associated herpesvirus (KSHV/HHV-8) and is traditionally classified into classic, African endemic, iatrogenic, and acquired immunodeficiency syndrome-associated forms[8,11,12]. Reported cases of BP with KS frequently involve patients with underlying immunosuppression, including HIV infection, chronic comorbidities (e.g., diabetes, hypertension, and chronic kidney disease)[13], or long-term exposure to immunosuppressive therapies. Another proposed mechanism is that immunosuppressants or corticosteroids may reactivate latent HHV-8 infection, promoting the development of KS. However, this hypothesis remains debated due to confounding factors such as drug type, dosage, and treatment duration[8,11,14]. Many reported cases involve prolonged systemic immunosuppression or moderate-to-high doses of corticosteroids. Furthermore, high cumulative exposure to superpotent topical corticosteroids (STS) may exert systemic immunosuppressive effects, particularly when combined with other therapies[15].

Dupilumab was initiated in combination with low-dose oral prednisone to minimize prolonged systemic corticosteroid exposure in our elderly patient. Corticosteroids were rapidly tapered to a minimal maintenance dose. The patient had no history of HIV infection, major chronic comorbidities, or previous immunosuppressive therapy. However, approximately 8 months after treatment initiation, progressive violaceous papules developed on the feet and were then diagnosed as KS. HHV-8 serological indicators were not tested either at baseline or after the diagnosis of KS, and the potential for latent HHV-8 infection or reactivation cannot be ruled out. This constitutes a limitation of the present study. Although concomitant STS use cannot be completely excluded as a contributing factor, current evidence linking STS, alone or in combination with low-dose systemic corticosteroids, to KS development remains limited. To our knowledge, no reports have described KS occurring after dupilumab treatment in patients with BP, suggesting a potential association.

Dupilumab is a fully human monoclonal antibody that targets the IL-4 receptor alpha, blocking IL-4 and IL-13 signaling. This mechanism downregulates eosinophil recruitment and suppresses B-cell activation[16,17]. The Th2 immune response plays a key role in BP pathogenesis; elevated levels of IL-4 and IL-13 derived from CD4⁺ and CD8⁺ T cells have been detected in both blister fluid and serum, accompanied by increased serum immunoglobulin E levels and eosinophilia[18-20]. These findings support the therapeutic rationale for dupilumab in BP. In clinical practice, dupilumab is often combined with conventional therapies such as corticosteroids or immunosuppressants. This may shorten treatment duration and reduce cumulative steroid exposure, lowering the risk of adverse events. Serious adverse events associated with dupilumab are relatively uncommon and mainly include soft tissue infections, conjunctivitis, psoriasiform dermatitis, and arthritis[21,22].

Following reports of dupilumab-associated head and neck dermatitis, Bangert et al[23] investigated the underlying immunological mechanisms and found that while dupilumab normalized downstream IL-4/IL-13 markers (CCL13, CCL17, CCL18, and CCL26), it also induced a pronounced type 22 immune signature characterized by increased IL-22 and aryl hydrocarbon receptor signaling, keratinocyte activation, and upregulation of IL-22 receptors. These findings suggest that inhibition of the Th2/Tc2 pathway by dupilumab may trigger compensatory immune shifts toward the Th1, Th17, and Th22 pathways. The occurrence of psoriasiform eruptions, conjunctivitis, and arthritis during dupilumab therapy further supports the hypothesis of immune deviation[24].

From a systems biology perspective, immune regulation involves complex signaling pathways and gene regulatory networks rather than isolated pathways. Whether through IL-4/IL-13 blockade or compensatory activation of IL-17 and IL-22 pathways, dupilumab-modulated signals are transmitted via modulation of the STAT3 pathway, leading to diverse biological effects[25]. One downstream outcome of STAT3 activation is increased IL-6 signaling, which can promote pro-inflammatory and pro-tumorigenic microenvironments. In KS, KSHV infection induces endothelial cells to produce cytokines such as IL-6, IL-10, and IL-13, which drive monocyte differentiation and polarization into tumor-associated macrophages that shape the tumor microenvironment. Tumor-associated macrophages can be polarized into M1-like (pro-inflammatory) and M2-like macrophages. The latter inhibits tumor immunity via IL-10 secretion and promotes tumorigenesis by activating the STAT3 signaling pathway[26]. STAT3, a positive regulator of viral productive replication, is activated in endothelial and primary effusion lymphoma cells during de novo and latent KSHV infection. This is critical for maintaining latently infected cell viability and efficient viral replication. The KSHV-encoded IL-6 homologue, frequently detected in latently infected primary effusion lymphoma cells, is key to KSHV-associated disease pathogenesis and immune escape[27,28]. It’s signaling through the gp130 receptor is the main mechanism of STAT3 activation[29]. Additionally, the KSHV-encoded IL-6 homologue promotes tumor angiogenesis by upregulating VEGF expression[30]. In summary, STAT3-related pathways play an important role in KS development.

Based on these observations, dupilumab-induced immune modulation could alter the local immune microenvironment via STAT3 signaling pathways, potentially facilitating KS development in susceptible individuals. However, given the complexity of immune regulatory networks, such effects are likely affected by multiple genetic and environmental factors rather than a single pathway. Furthermore, the uniqueness of this case does not exclude the possibility of individual genetic susceptibility. Due to the lack of verification of previous latent infection or viral reactivation of KSHV/HHV-8 in this case, the possibility that viral activation induces tumors cannot be ruled out. Therefore, the proposed mechanism remains speculative and requires further mechanistic investigation.

CONCLUSION

The association between BP and KS in this clinical context remains incompletely understood. It should be emphasized that the immune drift hypothesis proposed in this case is speculative and requires further exploration and verification. In this single case, we cannot rule out potential effects of low-dose systemic glucocorticoids, topical glucocorticoids, advanced age, and pre-existing latent HHV-8 infection. The evaluation criteria and impact of these factors require further verification. The potential contributions of immunosuppressive therapies (e.g., systemic and topical corticosteroids) according to their cumulative doses and treatment durations also warrant further investigation. Continued clinical observation and additional reports will be important for elucidating the long-term safety profile of dupilumab and optimizing therapeutic strategies for BP.