Desmoplakin I/II immunohistochemical staining may be a helpful tool in differentiating cutaneous graft versus host disease from the erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis spectrum disorders.

Cutaneous graft versus host disease (cGVHD) has substantial clinical and histopathologic overlap with erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). This overlap can make it difficult to distinguish these disorders in patients who have received hematopoietic transplants. We sought to evaluate the utility of Dp I/II immunohistochemical stain in differentiating EM/SJS/TEN and cGVHD in a large cohort. Skin biopsy specimens from patients with cGVHD (n = 58) and EM/SJS/TEN (n = 60) were evaluated for Dp I/II expression by immunohistochemistry. We found a statistically significant difference in Dp I/II staining between cGVHD (all grades) and EM/SJS/TEN (mean scores 1.62 and 2.14, respectively; p < 0.005), as well as between Grades 2 + 3 cGVHD and EM/SJS/TEN (mean scores 2.26 and 1.62, respectively; p < 0.005), while we did not find a significant difference between Grade 4 cGVHD and EM/SJS/TEN (mean scores 1.69 and 1.62, respectively; p = 0.71). Dp I/II immunostain may be useful for differentiating EM/SJS/TEN from Grade 2 and Grade 3 cGVHD, especially in clinically ambiguous cases without extracutaneous GVHD.

A case of eruptive lichen spinulosus after toxic epidermal necrolysis.

We report a case of a 13-year-old boy who presented with eruptive monomorphic white papules on the trunk and arms involving regions previously affected by toxic epidermal necrolysis (TEN). Biopsy revealed compact keratin involving the hair follicle and sparse mixed perivascular infiltrate, findings consistent with lichen spinulosus. Improvement was noted after treatment with ammonium lactate 12% lotion. While cutaneous dyschromia and xerosis are common after TEN, lichen spinulosus has not yet been described in the literature. It is important for providers to be aware of any potential cutaneous sequelae of TEN that can affect quality of life in order to best counsel their patients.

Epidermal necrolysis in the context of immuno-oncologic medication as well as kinase inhibitors and biologics.

BACKGROUND: Stevens-Johnson syndrome and toxic epidermal necrolysis are severe, primarily drug-induced reactions of skin and mucosa. Since they differ in the extent of skin detachment but not in etiology, they are grouped together as epidermal necrolysis (EN). Due to nationwide registration, representative data are available at the German Center for the Documentation of Severe Skin Reactions (dZh). Here, an increasing number of case notifications in the context with new immuno-oncologic drugs, kinase inhibitors and biologics have been observed. MATERIAL AND METHODS: Of 4,150 cases notifications between January 2003 and February 2019, 102 cases with exposure to these drug groups underwent systematic analysis, validation and causality assessment. RESULTS: Two cases of EN to vemurafenib were confirmed and one case to afatinib and pembrolizumab, respectively. In 14 EN cases other drugs - predominantly allopurinol or cotrimoxazole - were the causative agent. Fourteen cases were EN-like reactions: six bullous lichenoid drug eruptions (DE) to pembrolizumab (2), obinutuzumab, nivolumab, rituximab, infliximab/nivolumab, and eight multiforme-like DE to rituximab (2), adalimumab, ramucirumab, bevacizumab, vemurafenib, sorafenib (2). Lichenoid DE were differentiated from EN through histopathology and by the protracted course of EN, multiforme-like DE by variable skin manifestations with only sparse epidermolysis or mucosal involvement. CONCLUSIONS: A correct diagnosis is highly relevant in terms of prognosis and use of these drugs in malignoma treatment. Re-exposure is contraindicated in EN, but possible in other DE after rigorous risk-benefit evaluation.

Cutaneous Immune-Related Adverse Events Secondary to Immune Checkpoint Inhibitors and Their Management.

Immune checkpoint inhibitors (CPIs) are highly effective in the treatment of various cancers. Immunotherapy enhances antitumor activity by relieving inhibition of T cells responsible for immune surveillance. However, overactivation of T cells leads to immune-related adverse events (irAE), of which cutaneous adverse events are the most common. Examples include pruritus and maculopapular eruption most commonly, psoriasis and bullous dermatoses less commonly, and, rarely, severe, life-threatening eruptions such as Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis. Many of these are autoimmune in nature, and these may present de novo or as recurrence of pre-existing disease. In order to maximize the therapeutic potential of CPIs, it is essential to recognize and effectively manage cutaneous irAE, which can otherwise lead to treatment interruption or discontinuation. This review summarizes the presentation and management of dermatologic adverse events secondary to immune dysregulation as a result of immune checkpoint inhibitor therapy, including the most common (maculopapular eruption, pruritus, lichenoid dermatitis, and vitiligo), less common (psoriasis, bullous pemphigoid, erythema multiforme, eczematous dermatitis, alopecia areata, and granulo-matous and neutrophilic dermatoses), and severe (acute generalized exanthematous pustulosis [AGEP], drug reaction with eosinophilia and systemic symptoms [DRESS], and Stevens-Johnson syndrome or toxic epidermal necrolysis [SJS/TEN]), as well as exacerbation of pre-existing cutaneous autoimmune disease (subacute cutaneous lupus erythematosus, dermatomyositis, eosinophilic fasciitis, leukocytoclastic vasculitis, and scleroderma-like reaction).

Toxic epidermal necrolysis with systemic lupus erythematosus: case report and review of the literature.

Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are potentially fatal mucocutaneous diseases characterized by extensive necrosis and exfoliation of the epidermis. TEN and SJS are most often caused by various kinds of drugs. Other risk factors for SJS/TEN include pneumonia infection, HIV infection, genetic factors, underlying immune diseases, and tumors. SJS and TEN were first identified in 1922, but at present, a widely recognized view is that SJS and TEN represent phases in the continuous progress of the same disease. SJS/TEN has a very high mortality, but is rare, and cases of SJS/TEN combined with systemic lupus erythematosus (SLE) are even less common. Occasionally, acute cutaneous manifestations of SLE and SJS/TEN can be phenotypically similar, both causing extensive epidermal necrosis. In this paper, we present a recent case of a 32-year-old female SLE patient with a drug-induced (the health product, astaxanthin) TEN/SJS. To provide context to this case, we have reviewed relevant case studies published in English, accessed via PubMed databases. The search covers all published case studies from 1988 to 2019. We collected a total of 30 cases in the literature, and analyzed their characteristics from the aspects of gender, suspicious medication history, and treatment in order to expand clinicians' approach to diagnosis and treatment.

Sequential Blood Purification for Pediatric Fatal Toxic Epidermal Necrolysis: A Case Series.

BACKGROUND: Extracorporeal therapy that included therapeutic plasma exchange (TPE) or continuous hemofiltration (CHF) for toxic epidermal necrolysis (TEN) syndrome was used in small number of patients. We aimed to describe the sequential mode of combined application of CHF and TPE in 3 TEN patients with multiple organ dysfunction (MODS) in pediatric intensive care unit. METHODS: Three patients with fatal TEN received sequential CHF and TPE due to unsatisfactorily conventional treatments. CHF was initiated and performed on a daily basis with 35-50 mL/kg.h replacement fluid at the rate of 3-5 mL/kg.min blood flow. CHF was temporarily interrupted for TPE, which was performed with exchange 1-1.5-fold of one body calculated plasma volume in each section. RESULTS: All 3 fatal TEN (with >30% involvement of body surface and MODS) following unsuccessful treatment with corticosteroids and intravenous immunoglobulin. Antibiotics were suspected in the TEN-triggered drugs. The range number of TPE sessions was 3-5 and the duration of CHF was from 120 h to 202 h. After initiation of TPE and CHF, blistering with extensive epidermal necrosis halted and the skin re-epithelialized within 2 weeks. Serum C-reactive protein, procalcitonin, tumor necrosis factor-α , and interlukin-6 decreased and percentage of natural killer cells increased in surviving children. Two patients survived to discharge and one case died due to nosocomial infection with multidrug-resistant Acinetobacter baumannii. CONCLUSION: After sequential TPE and CHF, skin lesions and inflammatory response improved in TEN. Our result indicates extracorporeal therapy could be used as an alternative modality for fatal pediatric TEN.

A Rare Laryngeal Presentation of Stevens-Johnson Syndrome.

Stevens-Johnson syndrome (SJS) is a rare but severe mucocutaneous epidermolysis commonly triggered by medications. SJS is characterized by mucocutaneous lesions of the trunk, face, and limbs, as well as the oral cavity, gastrointestinal tract, and respiratory tract. Although uncommon, laryngeal involvement in SJS can lead to severe respiratory, phonatory and deglutitive complications. Providers caring for patients with SJS should maintain a high index of suspicion for laryngeal involvement and low threshold to solicit Otolaryngology consultation. Laryngeal complications can be more expediently managed when anticipated early in the course of disease. Laryngoscope, 131:2519-2522, 2021.

Toxic epidermal necrolysis-like acute cutaneous lupus erythematosus: two cases report.

Toxic epidermal necrolysis-like acute cutaneous lupus erythematosus (TEN-like ACLE) is a rare manifestation of systemic lupus erythematosus (SLE). Because of its rarity, little is known about this entity. In this report, we describe a case of two women previously diagnosed with SLE that presented TEN-like skin lesions. The common elements in both patients were the initial disposition of the lesions on the photoexposed areas, the positivity of Nikolsky´s sign, the discrete mucosal attrition compared to that observed during TEN, and the simultaneous appearance of dermatological lesions with an extra-cutaneous flare of lupus disease. The skin biopsy in both cases showed epidermal necrosis with an identification of lupus band on direct immunofluorescence. Systemic corticosteroids were used with a good evolution after 2 weeks. Skin damage is an indicator of disease activity, and careful search for extracutaneous involvement is obligatory to prevent further complications.

A Fatal Case of Toxic Epidermal Necrolysis Combined With Vanishing Bile Duct Syndrome and Hemophagocytic Lymphohistiocytosis.

This case report describes a case of fatal toxic epidermal necrolysis complicated by both vanishing bile duct syndrome and hemophagocytic lymphohistiocytosis due to Influenza B infection. Here we highlight the potential for complex morbidity secondary to underlying autoimmune hypersensitivity. Furthermore, the stepwise progression of these pathologies is noted, with the initial epidermal lesions first progressing to cholestatic injury and then subsequently to the hematologic manifestations.

Nivolumab-associated Stevens-Johnson syndrome in a patient with lung cancer.

Nivolumab is a fully human immunoglobulin G4 immune checkpoint inhibitor antibody approved for use in the treatment of several malignancies such as lung cancer. Cutaneous reactions to checkpoint inhibitors are frequent, appearing in approximately 40% of patients. Although most of the reactions are well tolerated, these drugs can lead to severe cutaneous adverse reactions, but a quick recognition of the symptoms can significantly decrease their mortality. In this case report, we describe a patient with metastatic squamous lung cell carcinoma suffering from nivolumab-induced Stevens-Johnson syndrome with severe skin denudation and mucosal involvement.

Comparative Study of Frozen and Permanent Section for Diagnosis of Toxic Epidermal Necrolysis.

Toxic epidermal necrolysis (TEN) is a severe, life-threatening mucocutaneous reaction, causing widespread sloughing of skin and mucosal surfaces. Accurate and prompt diagnosis is essential for optimal management and subsequent outcome. In this study, frozen sections were used as a rapid examination for initial diagnosis of TEN, and the frozen section diagnoses were assessed compared with permanent sections. One hundred patients of suspected TEN were referred to our burn unit, and 67 had sufficient clinical findings for frozen and permanent biopsies. The accuracy of frozen section relative to permanent section was evaluated by calculating diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value. And McNemar's tests were used to analyze the difference between the two methods. Fifty-two specimens were classified as TEN by frozen section, 51 of which were confirmed by permanent biopsy. The exception was diagnosed as bullous pemphigoid on permanent section. Fifteen specimens were read as negative for TEN on frozen slides but four were changed to positive by permanent biopsy. Overall, the diagnostic accuracy of frozen section was 92.5%, with sensitivity and specificity 92.7% and 91.7%, respectively. The positive predictive value, or coherence of positive diagnosis between the two methods, was as high as 98.1%, and the negative predictive value was 73.3%. The P value of McNemar's tests was .375, indicating there was no significant difference between the two biopsy methods. The data suggest that as a rapid histological assessment, frozen section is a reliable tool in the early diagnosis of TEN.

Toxic epidermal necrolysis occurring with immune checkpoint inhibitors.

Nivolumab and ipilimumab are immune checkpoint inhibitors (ICIs) used in the management of advanced malignancies including malignant melanoma. Although several cutaneous adverse events have been reported with these immunotherapy agents, toxic epidermal necrolysis (TEN) secondary to ICIs is rare. We report a 67-year-old man with TEN occurring during nivolumab and ipilimumab co-therapy and review published cases to highlight the challenges in recognizing and managing these patients. ICI-induced TEN can present atypically with delayed onset in comorbid, immunosuppressed patients with an associated high mortality rate. Prompt recognition and drug withdrawal are essential to improve outcomes. High dose systemic corticosteroid has also been recommended for the management of ICI-induced TEN, unlike other drug-induced TEN for which optimal immunomodulatory treatment is still debated.

Loss of Down Syndrome Critical Region-1 Mediated-Hypercholesterolemia Accelerates Corneal Opacity Via Pathological Neovessel Formation.

OBJECTIVE: The calcineurin-NFAT (nuclear factor for activated T cells)-DSCR (Down syndrome critical region)-1 pathway plays a crucial role as the downstream effector of VEGF (vascular endothelial growth factor)-mediated tumor angiogenesis in endothelial cells. A role for DSCR-1 in different organ microenvironment such as the cornea and its role in ocular diseases is not well understood. Corneal changes can be indicators of various disease states and are easily detected through ocular examinations. Approach and Results: The presentation of a corneal arcus or a corneal opacity due to lipid deposition in the cornea often indicates hyperlipidemia and in most cases, hypercholesterolemia. Although the loss of Apo (apolipoprotein) E has been well characterized and is known to lead to elevated serum cholesterol levels, there are few corneal changes observed in ApoE-/- mice. In this study, we show that the combined loss of ApoE and DSCR-1 leads to a dramatic increase in serum cholesterol levels and severe corneal opacity with complete penetrance. The cornea is normally maintained in an avascular state; however, loss of Dscr-1 is sufficient to induce hyper-inflammatory and -oxidative condition, increased corneal neovascularization, and lymphangiogenesis. Furthermore, immunohistological analysis and genome-wide screening revealed that loss of Dscr-1 in mice triggers increased immune cell infiltration and upregulation of SDF (stromal derived factor)-1 and its receptor, CXCR4 (C-X-C motif chemokine ligand receptor-4), potentiating this signaling axis in the cornea, thereby contributing to pathological corneal angiogenesis and opacity. CONCLUSIONS: This study is the first demonstration of the critical role for the endogenous inhibitor of calcineurin, DSCR-1, and pathological corneal angiogenesis in hypercholesterolemia induced corneal opacity.

Osimertinib-Associated Toxic Epidermal Necrolysis in a Lung Cancer Patient Harboring an EGFR Mutation-A Case Report and a Review of the Literature.

Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are life-threatening dermatologic adverse events in the same category, caused by a delayed-type drug hypersensitivity reaction. Although skin toxicity is common during treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), osimertinib-associated TEN is quite rare-thus far, only one report has been published from China. We report a case of an 80-year-old Japanese woman with lung adenocarcinoma harboring an EGFR-sensitizing mutation who was treated with osimertinib as the first-line treatment. Forty-six days after osimertinib induction, diffuse erythematous rash rapidly spread over the patient's trunk along with vesicles and purpuric macules; furthermore, she developed targetoid erythema on the face. Despite osimertinib discontinuation and corticosteroid treatment, diffuse erythema with Nikolsky's sign, general epidermal detachment, erosion and loose blisters developed over her entire body including the face. Based on her symptoms, TEN was diagnosed and thus, intravenous immunoglobulin was immediately administered for 4 days. The treatment ameliorated TEN-associated skin toxicity and caused epithelialization. Reports on osimertinib-associated SJS/TEN are scarce and only one report each on SJS and TEN from China is available. This is the first report of osimertinib-associated TEN from Japan. Cases of EGFR-TKI-associated SJS/TEN have been reported predominantly from Asian countries, suggesting ethnicity and genetic linkage play a role in the underlying mechanism.

Lip Synechia Resulting From Toxic Epidermal Necrolysis: A Rare Condition.

Toxic epidermal necrolyses represent a severe epidermolytic reaction characterized by cutaneous erythema and target lesions affecting >30% of the body surface, skin, and mucous membranes. Ulcerative lesions on the labial mucosa may evolve during healing, resulting in rare complications, such as lip adhesions. This report shows the successful treatment of a lip synechia resulting from the healing of mucosal lesions in a patient with toxic epidermal necrolysis caused by the use of Lamotrigine and Ibuprofen. Although the treatment of the presented lip synechia was simple, this sequela can be avoided by measures such as hydration, hygiene and lip lubrication.