Intraepidermal and subepidermal blistering with skin necrosis , possibly caused by etanercept in treatment of a patient with psoriasis

299 How to cite this article: Abreu Velez AM, Jackson BL, Howard MS. Intraepidermal and subepidermal blistering with skin necrosis, possibly caused by etanercept in treatment of a patient with psoriasis. Our Dermatol Online. 2015;6(3):299-303. Submission: 22.01.2015; Acceptance: 12.03.2015 DOI:10.7241/ourd.20153.80 Intraepidermal and subepidermal blistering with skin necrosis, possibly caused by etanercept in treatment of a patient with psoriasis


INTRODUCTION
Enbrel © (Etanercept) is a biologic medical product that is used to treat autoimmune diseases by interfering with tumor necrosis factor (TNF; a soluble inflammatory cytokine) by acting as a TNF inhibitor [1].Etanercept has U.S. FDA approval to treat rheumatoid, juvenile rheumatoid and psoriatic arthritis, plaque psoriasis and ankylosing spondylitis [1].Etanercept is a fusion protein produced by recombinant DNA.It fuses the TNF receptor to the constant end of the IgG1 antibody [1].On May 2, 2008, the FDA placed a black box warning on Etanercept, due to a number of complications associated with the drug in postmarketing reports of serious infections and sepsis, including fatalities.Tumour necrosis factor (TNF)-α is a proinflammatory cytokine that may induce antiapoptotic proteins and endothelial cell activation factors in psoriasis, and therefore is commonly used in dermatology practices.It has also being proposed that Etanercept may inhibit neovascularisation in psoriatic lesions

CASE REPORT
A 78 year old Caucasian female had been recently treated with Etanercept for plaque psoriasis.A week later the patient presented excoriated, necrotic patches and plaques on the face, buttocks, chest, abdomen and extremities.Skin biopsies for hematoxylin and eosin (H&E) and immunohistochemistry (IHC) review, as well as direct immunofluorescence (DIF) were obtained.The Etanercept administration was halted, and topical steroids were given to the patient resulting in improvement of the necrotic lesions.

Microscopic Description
A: Examination of the H&E tissue sections demonstrated focal, confluent parakeratosis within the stratum corneum.In addition, scattered collections of neutrophils were seen within the stratum corneum.Overall, the epidermis displayed minimal psoriasiform hyperplasia; the stratum granulosum was focally attenuated.Some focal epidermal spongiosis was seen.In focal areas, the epidermis was also ulcerated, with collections of neutrophils and serum scale crust present within the ulcer bases.Both intraepidermal and subepidermal blisters and clefts were seen.Dermal cellulitis is not present.Within the dermis, a mild, perivascular infiltrate of lymphocytes, histiocytes and neutrophils was present.Eosinophils were rare.No evidence of a neoplastic process was seen.Special stained slides were reviewed; the positive controls stained appropriately.The Gram special stain revealed collections of Gram positive, bacterial coccal organisms within the serum scale crust areas.

Immunohistochemistry (IHC)
As expected, myeloperoxidase and CD15 were very positive in the blister, around the edges of the blisters and in the crust material.CD45 was positive in some areas of the epidermal corneal layer, within the blisters and around upper dermal blood vessels.CD8 was positive mainly around the upper dermal inflammatory infiltrate.In the upper and intermediate dermal blood vessels, some markers such VEGF and von Willembrand factor seemed to be overexpressed.We also noted that P53 and BCL-10 were positive in the epidermis, but with strong expression around the blister edges and in some focal BMZ areas.Factor XIIIa was positive around the edges of the blisters (Fig. 1).
Our findings indicate that Etanercept did possibly trigger the patient's secondary blistering and ulceration reaction due to involvement of the dermal vasculature.Moreover, this medication could not stop the anticorneal antibodies that were still being seen on the DIF.Given the fact that we observed some superinfection with Gram positive cocci in the ulcers, Etanercept could have some immunosupressant role in the psoriatic plaques.Other notable observations are that the BCL10 and P53 markers seem to play some role in development of the blisters, possibly by some apoptotic regulatory role that remains unknown.
Given our data, it is important to consider that there are other anti-TNF monoclonal antibodies similar to Etanercept, including Infliximab®, Adalimumab®, Certolizumab®, Golimumab® and Pegsunercep®.Thus, these medications may act as putative triggers in some secondary reactions in patients treated for plaque psoriasis.

CONCLUSIONS
We report an unknown reaction, possibly triggered by Etanercept and featuring intraepidermal and subepidermal blistering with skin necrosis.The incidences of inflammatory skin reactions due and/ or related to Etanercept need to be considered when patients are using this medication suddenly develop dermatologic side effects, including those described here.

CONSENT
The examination of the patient was conducted according to the Declaration of Helsinki principles.

Figure 1 :
Figure 1: (a and b) H & E stain showing the epidermal corneal layer with necrosis and a subcorneal blister (black arrow), and also some subepithelial blisters (red arrows), (100X), In b, higher magnification of a, showing the subepithelial blisters (black arrows) (200X).c.DIF, using anti-human FITC conjugated fibrinogen antibody positivity, with pseudo-basement membrane deposits in a serrated manner (white staining; white arrows) as well as staining against the upper dermal blood vessels (white staining; red arrow).d.IHC double staining, using anti-human CD15 in brown and anti-CD45 in red.The photomicrograph highlights an amalgamation of the positivity of both markers in the crust (yellow arrow), as well as on the blister floor (black arrow).e. IHC staining with CD8 antibody, showing positive staining in an upper dermal perivascular infiltrate (brown staining; red arrow).f.IHC double staining, using anti-human myeloperoxidase in brown and anti-von Willembrand factor in red.The photomicrograph highlights damage to dermal blood vessels and (red staining; black arrow) and the presence of myeloperoxidase in the crust(brown staining; black arrow).