Characterization of T-Helper Immune Phenotype in Symmetrical Drug-Related Intertriginous and Flexural Exanthema (SDRIFE) Endorses a Delayed-Type Hypersensitivity Reaction.

ABSTRACT: Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) is a cutaneous drug eruption with a characteristic distribution of erythema on the gluteal/inguinal region and intertriginous areas with unclear pathogenesis. In this study, we aimed to characterize the T-helper immune phenotype in SDRIFE in comparison with psoriasis and eczema to further the understanding of the pathophysiology and immune response of this rare disorder. Immunohistochemical staining was performed on 9 skin biopsies each from SDRIFE, psoriasis, and eczema using immunohistochemistry for CD3 and dual CD4/T-bet, CD4/GATA3, and CD4/RORC to quantify the percentage of Th1, Th2, and Th17 cells, respectively. A significant difference was detected in the average percentage of Th1 between all 3 groups with the highest percentage of Th1 cells seen in psoriasis, followed by SDRIFE and eczema. SDRIFE showed significantly lower Th2 expression as compared to both psoriasis and eczema. There was a trend towards a higher average percentage of Th17 in psoriasis and SDRIFE, and the ratio of Th17:Th2 was significantly higher in samples of SDRIFE compared with both eczema and psoriasis. The findings characterize SDRIFE as a Th1 and possibly Th17-driven process, which could inform future therapeutic options and substantiate the model of SDRIFE as a delayed-type hypersensitivity reaction.

A Rare Skin Rash: Linezolid-Induced Purpuric Drug Eruption without Vasculitis in a Puerto Rican Man.

BACKGROUND Cutaneous adverse drug reactions are the skin's response to a systemic exposure to drugs. Linezolid is an oral oxazolidine used to treat methicillin-resistant Staphylococcus aureus infections. Even though it has well-known adverse effects, purpuric cutaneous adverse drug reactions to linezolid have been scarcely described. This report is of a Puerto Rican man in his 80s who developed an extensive purpuric drug eruption secondary to linezolid use. Clinicians should be aware of this phenomenon, since prompt identification and discontinuation of the agent are essential for recovery. CASE REPORT An 89-year-old Puerto Rican man was given oral linezolid therapy for healthcare-associated pneumonia and developed a widespread, purpuric cutaneous eruption 5 days into therapy. His condition prompted immediate discontinuation of the drug. Forty-eight hours after stopping the medication, he visited the Emergency Department. Abdominal punch biopsy revealed a superficial and perivascular lymphocytic infiltrate with dermal eosinophils, a pathologic finding consistent with a purpuric drug eruption. This allowed for a timely diagnosis, exclusion of other mimickers, such as cutaneous vasculitis, and effective management. CONCLUSIONS Cutaneous adverse drug reactions to linezolid have been scarcely reported in the literature. Due to the low incidence of this manifestation, the identification of the causative agent and accompanying treatment may be delayed. Mainstays in therapy are avoidance of the offending agent and treatment with corticosteroids, antihistamines, barrier ointments, and oral analgesics. Primary healthcare providers should be aware of linezolid-induced cutaneous manifestations, diagnostic clues, and treatment options so they can rapidly identify and effectively treat such complications.

Lenalidomide-induced symmetrical drug-related intertriginous and flexural exanthema.

Symmetric drug-related intertriginous and flexural exanthema (SDRIFE) is a cutaneous drug reaction that presents with symmetrical erythema in the flexures. The reaction typically appears hours-to-days after drug exposure but has been reported to occur months after drug initiation. Diagnostic criteria include cutaneous reaction after exposure to a systemic drug, erythema of the gluteal region and/or V-shaped erythema of the inguinal areas, involvement of an additional intertriginous site, symmetry, and absence of systemic involvement. The rash typically presents as macular erythema. However, variations in morphology have been reported including papules, pustules, vesicles, and bullae. The histopathology of SDRIFE is non-specific and the diagnosis is made clinically. Cessation of the causative drug leads to gradual rash resolution. Beta-lactam antibiotics are the most implicated medications but case reports describe SDRIFE following monoclonal antibodies, chemotherapeutic agents, and various other medications. We present a patient with SDRIFE secondary to lenalidomide, an immunomodulatory agent. This case highlights the importance of considering SDRIFE in the differential diagnosis of patients presenting with intertriginous erythema.

Halogen halos: Report of an early histopathologic finding in iododerma.

Iododerma is a rare cutaneous eruption that manifests after exposure to iodine-containing compounds, with few cases reported in the literature. Previous reports of this halogenoderma have described acellular halos simulating cryptococcus on histopathological examination but there is a paucity of reports of biopsies taken early in the disease course. We present a case of a 78-year-old patient who developed a papular eruption after receiving iodinated contrast. A skin biopsy taken within 24 h of the eruption showed a neutrophilic infiltrate with cryptococcal-like acellular haloed structures, indicating that the diagnostic finding may be found early in the disease course.

Neutrophilic fixed drug eruption, a histopathologic variant or an expected finding?-A report of two cases and review of the literature.

Fixed drug eruption (FDE) is an adverse drug reaction characterized by recurrent circumscribed lesions at the same location upon re-exposure to the culprit medication, resulting in distinct postinflammatory hyperpigmentation. Histopathologically, FDE demonstrates a predominantly lymphocytic interface or lichenoid infiltrate with basal cell vacuolar changes and keratinocyte dyskeratosis/apoptosis. The term "neutrophilic fixed drug eruption" has been used to describe cases in which the inflammatory infiltrate is predominantly neutrophilic. The infiltrate can extend deeper in the dermis, potentially mimicking a neutrophilic dermatosis such as Sweet syndrome. We present two cases and review the literature to discuss the possibility that a neutrophilic inflammatory infiltrate may be an expected finding in FDE, rather than a histopathologic variant.

MULTIFOCAL FIXED DRUG ERUPTION MIMICKING ACQUIRED DERMAL MELANOCYTOSIS.

Fixed drug eruptions (FDEs) are adverse drug reactions manifesting in the skin after exposure to a certain drug. The lesions can manifest as single or multiple eruptions followed by a post-inflammatory hyperpigmentation. The condition is very common among the young adult population and can be located on different parts of the body: the trunk, extremities, face, lips, etc. We report a case of a multifocal FDE following oral intake of Loratadine, Cetirizine dihydrochloride, Ibuprofen and/or Acetylsalicylic acid. Patch testing was recommended but later on declined by the patient. However, a small punch biopsy confirmed the diagnosis of multifocal fixed drug eruption. The lesions are often misdiagnosed or mistaken for other skin conditions. Differential diagnosis with an acquired dermal melanocytosis or other cutaneous eruptions could be done. Therefore, a brief review of the above-mentioned medications in the pathogenesis of the condition will be discussed.

Rapidly progressing generalized bullous fixed drug eruption after the first dose of COVID-19 messenger RNA vaccination.

Generalized bullous fixed drug eruption (GBFDE) is a rare type of life-threatening severe cutaneous adverse reaction that is considered a medical emergency because of its potential lethality. Currently, only a few cases of bullous adverse reactions have been reported after coronavirus disease 2019 (COVID-19) vaccination. We describe a patient with distinct clinical, histopathological, and immunological findings that are consistent with severe GBFDE, after Pfizer messenger RNA COVID-19 vaccination. An 83-year-old man presented with a fever and well-demarcated multiple erythematous patches that occurred only 4 h after receiving the first dose of COVID-19 Pfizer vaccination. Over the next few days, the patches became generalized and turned into blisters covering approximately 30% of the body surface. The patient was started on intravenous methylprednisolone and oral cyclosporine. There were no additional blistering lesions after 10 days of treatment, prompting a gradual dose reduction. Our case suggests that a stepwise vaccination adhering to the standard dosing schedule should be warranted with close monitoring for possible significant side effects.

The diverse landscape of dermatologic toxicities of non-immune checkpoint inhibitor monoclonal antibody-based cancer therapy.

BACKGROUND: Since their first approval 25 years ago, monoclonal antibodies (mAbs) have become important targeted cancer therapeutics. However, dermatologic toxicities associated with non-immune checkpoint inhibitor (non-ICI) mAbs may complicate the course of cancer treatment. Data on the incidence and types of these reactions are limited. METHODS: A comprehensive review was conducted on dermatologic toxicities associated with different classes of non-ICI mAbs approved for treatment of solid tumors and hematologic malignancies. The review included prospective Phase 1, 2, and 3 clinical trials; retrospective literature reviews; systematic reviews/meta-analyses; and case series/reports. RESULTS: Dermatologic toxicities were associated with several types of non-ICI mAbs. Inflammatory reactions were the most common dermatologic toxicities, manifesting as maculopapular, urticarial, papulopustular/acneiform, and lichenoid/interface cutaneous adverse events (cAEs) with non-ICI mAbs. Immunobullous reactions were rare and a subset of non-ICI mAbs were associated with the development of vitiligo cAEs. CONCLUSION: Dermatologic toxicities of non-ICI mAbs are diverse and mostly limited to inflammatory reactions. Awareness of the spectrum of the histopathologic patterns of cAE from non-ICI mAbs therapy is critical in the era of oncodermatology and oncodermatopathology.

Acute iododerma presenting as cryptococcoid neutrophilic dermatosis: A clinicopathological pitfall and interesting findings gleaned from a review of the literature.

Iododerma is an uncommon dermatosis caused by excessive iodine exposure and is associated with significant morbidity and mortality. Because of its heterogenous clinical presentation and variable histopathological findings, which depend on the time the skin biopsy is performed, the diagnosis of iododerma is often delayed. We report a rare case of acute iododerma in a woman with end-stage diabetic nephropathy with antecedent radioiodine contrast exposure, presenting histopathologically as cryptococcoid neutrophilic dermatosis (CND). We underscore important clinicopathological pitfalls to avoid misdiagnosis with similar overlapping entities such as Sweet syndrome, review all published cases of CND and draw novel insights into its associated entities.

Temporal shifts of the microbiome associated with antibiotic treatment of purpuric drug eruptions related to epidermal growth factor receptor inhibitors.

BACKGROUND: Epidermal growth factor receptor (EGFR) inhibitors are selective and effective treatments for cancers with relevant mutations. Purpuric drug eruptions are an uncommon but clinically significant dermatological side effect related to EGFR inhibitor use that are associated with positive bacterial cultures and responsive to antibiotic treatment. However, the longitudinal temporal shifts in the skin microbiome that occur before and after antibiotic treatment of purpuric drug eruptions remain largely unknown. OBJECTIVES: To characterize temporal changes in the skin and mucosal microbiomes before and after antibiotic treatment of EGFR inhibitor-related purpuric drug eruptions. METHODS: Twelve patients who experienced EGFR inhibitor-related purpuric drug eruptions were recruited from a dermato-oncology clinic in Taiwan from May 2017 to April 2018. Swabs were obtained from skin lesions and the nasal mucosa before and after antibiotic treatment of purpuric drug eruptions. After the amplification and sequencing of bacterial 16S rRNA genes, the diversity and compositions of microbiomes sampled at different time points were compared. RESULTS: The alpha diversity (represented by the Shannon index) of the skin microbiome increased significantly in the recovered phase of purpuric drug eruptions compared with that of the active phase. By contrast, the nasal microbiome showed no significant change in alpha diversity. The relative abundance of Staphylococcus significantly decreased in samples from skin of the recovered phase, which was confirmed by analysis of compositions of microbiomes (ANCOM) and the ALDEx2 analysis packages in R. CONCLUSIONS: The cutaneous microbiome of purpuric drug eruptions showed a significant increase in alpha diversity and a decrease in the relative abundance of Staphylococcus following antibiotic treatment. These findings may help guide antimicrobial therapy of this EGFR inhibitor-related condition.

Cross-reactivity between nonsteroidal anti-inflammatory drugs in fixed drug eruption: Two unusual cases and a literature review.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the main causes of fixed drug eruption (FDE). Cross-sensitivity between chemically unrelated NSAIDs has been rarely described in FDE. We report herein two cases of NSAID-induced FDE confirmed by oral provocation test (OPT) with a literature review. Case 1 is a 49-year-old woman who took mefenamic, naproxen and acetaminophen for lumbago. On the second day, she noticed three erythematous plaques, located in the upper lip, chin and the right hand, which faded spontaneously, leaving residual patches. Three months later, she took mefenamic acid with reactivation of the same plaques. She received naproxen. On the same day, she exhibited a reactivation of lesions with the development of a new one. These lesions have disappeared leaving hyperpigmented sequelae. After negative patch test to naproxen, an OPT was performed with positive reaction, observed on the third day. To establish the cross-reactivity, she underwent OPTs, which gave positive results to indomethacin, ketoprofen and tiaprofenic acid. Case 2 is a 52-year-old woman who presented painful dusky-red macules, located in the right and left wrists, 24 hours after taking mefenamic acid. She described two similar events that occurred in the past with an undefined drug and piroxicam. Patch tests to lysine acetylsalicylate, mefenamic acid, piroxicam, naproxen and celecoxib were negative. OPTs to the same NSAIDs gave positive results to lysine acetylsalicylate, piroxicam and mefenamic acid. Thirteen case reports, seven case series and one retrospective analysis, including cases with confirmed cross-reactivity between NSAIDs, were reported in literature. Clinicians should be aware of such phenomenon.

Dose-dependent, non-pigmenting fixed drug eruption with eczematous lesions induced by bosutinib: case report.

Bosutinib, widely used as a primary treatment for chronic myeloid leukemia (CML), is known to frequently cause cutaneous drug eruptions. Fixed Drug Eruption (FDE) is common, typically presenting as recurrent lesions that heal with residual hyperpigmentation. Diagnosing FDE, especially Non-Pigmenting Fixed Drug Eruption (NPFDE), is often challenging. A correlation exists between the dosage of certain medications, such as levetiracetam, and the emergence of drug eruptions. This report details a unique case of dose-dependent NPFDE caused by bosutinib. In managing cutaneous drug eruptions, particularly when the causative drug is crucial for treatment, a strategy of tapering the dosage should be considered.

Flagellate dermatitis in bleomycin chemotherapy: a causality?

Flagellate dermatitis is a relatively rare reaction to toxicity. It appears as skin lesions with erythematous patches or papules of linear, multiple, flagellate structures. Flagellate dermatitis can be triggered by several causes, which are most commonly associated with bleomycin. This paper reports two cases of flagellate dermatitis, one in a patient with germ cell carcinoma and another in a patient with osteosarcoma who were both diagnosed with flagellate dermatitis after the administration of bleomycin.

Fixed drug eruption from atezolizumab.

Fixed drug eruption (FDE) is a cutaneous drug reaction that tends to recur in the same area (fixed location) upon re-exposure to the offending agent. We present a 48-year-old woman with FDE being treated for metastatic breast cancer with atezolizumab. We believe this is the first reported case of FDE secondary to atezolizumab.

Neutrophils in Fixed Drug Eruptions: Correction of a Mistaken Hypothesis.

ABSTRACT: Classical histopathological findings of fixed drug eruption (FDE) include a lichenoid/interface dermatitis and perivascular infiltrate in the upper and deep dermis composed of lymphocytes and eosinophils accompanied by pigment incontinence. The presence of neutrophils is also an established finding but is less investigated. Sporadic cases of "neutrophilic FDE" have been reported and suggested as a separate entity, a rare variant, or an early stage of the condition. In this article, we report 16 cases of FDE with quantitative analysis showing that neutrophils are relatively common in FDE (68.8%) and that cases with abundant neutrophils had a significantly shorter onset-to-biopsy interval (3.7 vs. 16.9 days, P < 0.023). Our findings support that neutrophilic FDE more likely represents the early phase of FDE rather than a different entity. The presence of neutrophils expands the histopathological differential diagnosis of FDE to include neutrophilic dermatosis, signifying the value of clinical correlation.

Clinical and direct immunofluorescence characteristics of cutaneous toxicity associated with enfortumab vedotin.

Enfortumab vedotin (EV), a novel antibody-drug conjugate approved for metastatic urothelial carcinoma, causes a variety of cutaneous adverse reactions. We present two cases of bullous eruptions following treatment with EV, both demonstrating IgG deposition on direct immunofluorescence (DIF) correlating to the location of nectin-4 in the epidermis. This suggests that the IgG component of EV binding to nectin-4 in keratinocytes is likely a primary contributor to the high rates of cutaneous toxicity.

Eczematous drug eruption in patients with psoriasis under anti-interleukin-17A: does interleukin-22 play a key role?

BACKGROUND: Eczematous drug eruption (EDE) is a spongiotic skin reaction in response to systemic medications. To date, EDE has been described in patients treated with anti-interleukin (IL)-17A monoclonal antibodies with a prevalence of 2.2%-12.1%. AIM: To describe the clinical and histological features and the skin cytokine milieu in patients with EDE induced by anti-IL-17A biologics. METHODS: This was a prospective study, enrolling patients with psoriasis who developed EDE during treatment with two anti-IL-17 biologics, ixekizumab and secukinumab, from June 2019 to April 2021. Skin biopsies were taken from all patients: a 5-mm lesional biopsy (LB) and a 3-mm nonlesional biopsy (NLB). The LB sample was split into two parts, one for histological examination and the other for cytokine profile evaluation. RESULTS: During the study period, treatment with an anti-IL-17A drug was given to 289 patients of whom 8 (2.8%) developed EDE during the treatment. Histopathological evaluation suggested a diagnosis of spongiotic dermatitis in all eight patients. Cytokine gene expression showed a predominance of T helper (Th)2/Th22 cytokines in EDE lesions with a large increase in IL-4, IL-22 and S100A7 levels in both LB and NLB samples compared with healthy skin. IL-4, IL-22 and S100A7 were significantly higher in LB compared with NLB samples. IL-26 levels were also significantly increased in both LB and NLB compared with healthy skin, whereas low levels of IL-23A were found in both LB and NLB. CONCLUSION: Eczematous drug eruption skin lesions have mainly Th2/Th22 features, with IL-22 playing a major role in their pathogenesis. EDE seems to be the result of an imbalance towards a Th2/Th22 response, secondary to the blockade of IL-17A activity.