Erythrodermic Psoriasis in the Context of Emerging Triggers: Insights into Dupilumab-Associated and COVID-19-Induced Psoriatic Disease

Abstract

Psoriasis is a chronic immune-mediated inflammatory skin disorder characterized by keratinocyte hyperproliferation, impaired epidermal barrier function, and immune dysregulation. The Th17/IL-23 axis plays a central role in its pathogenesis, promoting the production of key pro-inflammatory cytokines such as IL-17, IL-23, and TNF-α, which sustain chronic inflammation and epidermal remodeling. Emerging evidence suggests that SARS-CoV-2 may trigger new-onset or exacerbate existing psoriasis, likely through viral protein-induced activation of toll-like receptors (TLR2 and TLR4). This leads to NF-κB activation, cytokine release, and enhanced Th17 responses, disrupting immune homeostasis. Erythrodermic psoriasis (EP), a rare and severe variant, presents with generalized erythema and desquamation, often accompanied by systemic complications, including infection, electrolyte imbalance, and hemodynamic instability. In a murine model of SARS-CoV-2 infection, we found notable cutaneous changes: dermal collagen deposition, hair follicle destruction, and subcutaneous adipose loss. Parallel findings were seen in a rare clinical case (only the third reported case) of EP in a patient with refractory psoriasis, who developed erythroderma after off-label initiation of dupilumab therapy. The patient's histopathology closely mirrored the changes seen in the SARS-CoV-2 model. Histological evaluations also reveal similarities between psoriasis flare-ups following dupilumab treatment and cutaneous manifestations of COVID-19, suggesting a shared inflammatory pathway, potentially mediated by heightened type 1 and type 17 responses. This overlap raises the possibility of a latent connection between SARS-CoV-2 infection and increased psoriasis severity. Since the introduction of COVID-19 vaccines, sporadic cases of EP have been reported post-vaccination. Although rare, these events imply that vaccine-induced immune modulation may influence psoriasis activity. Our findings highlight a convergence of inflammatory mediators-including IL-1, IL-6, IL-17, TNF-α, TLRs, and NF-κB-across three triggers: SARS-CoV-2, vaccination, and dupilumab. Further mechanistic studies are essential to clarify these relationships and guide management in complex psoriasis cases.

Keywords: COVID-19; IL-4; SARS-CoV-2; T-cell; dupilumab; erythrodermic psoriasis; monoclonal antibodies; psoriasis.

Figure 1

Diffuse erythema and desquamation were observed, accompanied by features of age-related skin changes, all consistent with a diagnosis of severe cutaneous erythrodermic psoriasis.

Figure 2

Histopathological findings of the skin biopsy (H\&E stain). The skin biopsy reveals marked thickening of the epidermal layer (yellow star), accompanied by notable intercellular fluid accumulation (yellow arrows). Dense inflammatory cell infiltration is observed (black arrows), along with increased collagen deposition around the capillaries (green arrows). Extensive collagen deposition within the dermis indicates ongoing fibrotic remodeling and tissue injury (red arrows).

Figure 3

Histopathological findings of the skin biopsy (H&E stain). The yellow star indicates a region of intense inflammatory cell infiltration within the dermal layer. These inflammatory foci are surrounded by varying degrees of collagen deposition, suggestive of ongoing dermal remodeling and fibrotic response.

Figure 4

Histopathological findings of the skin biopsy (H&E stain). The yellow star indicates a region of intense inflammatory cell infiltration within the dermal layer and contains various inflammatory cells and tissue congestion. The yellow star indicates the smooth muscle with various cellular deposits, mild congestion, and collagen accumulation. The black arrow shows the nest of collage deposition, whereas the blue arrow reveals the interstitial fluid deposition and formation of bullae like pictures within the dermal layer.

Figure 5

Mice histopathological findings of the skin biopsy (H&E stain). Panel (A): Control group (non-infected mice). The blue star highlights the normal hypodermis, while the black arrow indicates intact hair follicles. The red arrow denotes normal interstitial supportive tissues and cellular components. The blue arrow marks the normal well-organized epidermal layer. Panel (B): Long-term (12-month) SARS-CoV-2-infected mice. The star identifies a distorted hypodermis exhibiting fibrotic changes and the shrinkage of subcutaneous adipose tissue. The blue arrow points to the marked distortion and thinning of the epidermal layer. The red arrow highlights significant collagen deposition and inflammatory cell infiltration, with the severe disruption of normal dermal architecture.

Figure 6

Various triggers (e.g., COVID-19 infection and vaccines, or other infections) initiate downstream signaling through dendritic cells, leading to the release of cytokines such as IL-23 and TNF, which stimulate T-cells. Activated T helper 1 (Th1) cells then produce pro-inflammatory cytokines like IFN-γ and TNF, further amplifying the immune response. Mast cells contribute additional cytokines, including IL-6 and TNF, reinforcing the inflammatory cascade. This cascade results in keratinocyte proliferation and inflammation in the epidermis, causing psoriatic plaque formation and the exacerbation of symptoms. Moreover, acute-on-chronic activation of fibroblasts by TGF-β promotes collagen deposition in the dermis, potentially contributing to tissue remodeling or fibrosis in chronic cases.