The incidence of severe cutaneous drug eruptions during the COVID-19 period in Sweden has not been studied previously. Our aim was to compare the incidence of these skin reactions in a Swedish health region during the COVID-19 pandemic period with that of the year after: we conducted a retrospective, observational cohort study using data from a national registry of patients diagnosed with cutaneous drug eruptions during the pandemic in Sweden. We included the number of patients diagnosed with severe cutaneous drug eruptions at the Department of Dermatology in the Jonkoping health region during the COVID-19 pandemic (1 April 2020 to 31 March 2021) and the reference period (1 April 2021 to 31 March 2022). We examined the monthly occurrences of cutaneous drug eruptions in three dermatology clinics within the Jonkoping health region. The frequency of these eruptions was determined for two distinct time periods: during the pandemic and post-pandemic. The study included 102 patients with cutaneous drug eruptions: 29 patients were diagnosed during the COVID-19 pandemic period and 73 were diagnosed during the reference period. The difference in the number of cutaneous drug eruptions cases (p-value = 0.0001, 95% CI 1.4995-3.5500, OR 2.3072) during the pandemic period compared to the post-pandemic period was significant. To our knowledge, the impact of the pandemic on cutaneous drug eruptions has not been investigated in EU countries. The increasing and differentiation of the number of diagnosed cutaneous drug eruptions cases after the pandemic could be explained by the removal of COVID-19 restrictions and the more frequent health-seeking behavior during the post-pandemic period.

In this systematic review, we anticipated in summarizing clinical features, histopathological hallmarks, and possible pathology behind the maculopapular skin eruptions occurring in Covid-19 patients. A literature search was executed using MEDLINE/PubMed and Embase databases for articles published till 20 November 2020. All eligible articles including observational studies, case reports, and case series reporting the maculopapular skin lesion in Covid-19 patients were included. Data were obtained for 354 Covid-19 patients presenting with maculopapular lesions from 40 studies. The mean age of these patients was 53 years, and with 42% of them being male. These maculopapular lesions differed considerably in terms of distribution and appearance, ranging from diffuse erythematous maculopapular lesions to scattered erythematous macules coalescing into papules to maculopapular lesions in plaques. The mean duration of the lesion was 8 days. These lesions were frequently localized on trunks and extremities. Superficial perivascular dermatitis with lymphocytic infiltrate was a histopathological hallmark of these lesions. As these skin lesions may have a possible association with diagnosis, management, prognosis, and severity of the disease, all health practitioners need to be well acquainted with these Covid-19 skin lesions. Also, in the middle of this worldwide pandemic, early identification of this eruption may help manage this infection's further spread.

Cutaneous eruption is a common drug-adverse reaction, characterised by keratinocytes inflammation and apoptosis. Shuanghuanglian injeciton (SHLI) is a typical Chinese medicine injection, which is used to treat influenza. It has been reported that SHLI has the potential to induce cutaneous adverse eruptions. However, the mechanisms remain unclear. Since desmoglein 1 (DSG1) shows a crucial role in maintaining skin barrier function and cell susceptibility, we assume that DSG1 plays a critical role in the cutaneous eruptions induced by SHLI. In our study, retinoic acid (RA) was selected to downregulate the DSG1 expression, and lipopolysaccharide (LPS) was first used to identify the susceptibility of the DSG1-deficiency Hacat cells. Then, SHLI was administrated to normal or DSG1-deficient Hacat cells and mice. The inflammatory factors and apoptosis rate were evaluated by RT-PCR and flow cytometry. The skin pathological morphology was observed by hematoxylin and eosin (HE) staining. Our results show that treated only with SHLI could not cause IL-4 and TNF-α mRNA increases in normal Hacat cells. However, in the DSG1-deficient Hacat cells or mice, SHLI induced an extreme increase of IL-4 and TNF-α mRNA levels, as well as in the apoptosis rate. The skin tissue showed a local inflammatory cell infiltration when treated with SHIL in the DSG1-deficient mice. Thus, we concluded that DSG1 deficiency was a potential causation of SHLI induced eruptions. These results indicated that keratinocytes with DSG1 deficiency were likely to induce the cutaneous eruptions when stimulated with other medicines.

With the approval of the adjuvanted recombinant zoster vaccine (RZV; Shingrix, GSK) in October 2017, GSK established enhanced safety surveillance measures to allow prompt identification of potential safety signals not observed during clinical development. In Germany, cases of vesicular and bullous cutaneous eruptions following RZV vaccination were reported.

Telaprevir used as a protease inhibitor against hepatitis C virus is frequently associated with cutaneous adverse reactions. To explore a histological biomarker of cutaneous adverse events induced by telaprevir, we systematically searched for genes that were dysregulated by telaprevir in normal human epidermal keratinocytes (NHEKs). Microarray analysis and real-time polymerase chain reaction (PCR) revealed the significant increase in the expression of S100 calcium-binding protein A2 (S100A2) gene following treatment of NHEKs with telaprevir. Immunohistochemical analysis demonstrated that the expression of S100A2 was dominant in the spinous layer of the epidermis in patients with telaprevir-mediated severe-type drug eruptions and limited to the basal layer of the epidermis in healthy subjects. Furthermore, S100A2 expression increased after treatment with trichloroethylene and other medications, and the degree of S100A2 expression correlated with the severity of cutaneous adverse events. S100A2 expression also significantly increased in the skin of patients with atopic dermatitis and psoriasis. Taken together, S100A2 is highly expressed in the epidermis under inflammatory conditions and drug eruptions and may serve as a marker for keratinocyte damage in response to any inflammatory or toxic condition.

Background: Sparse data are available on rates of drug-induced pruritus, a well-recognized adverse reaction. We sought to assess relative rates of pruritus associated with commonly prescribed medications. Methods: Using the electronic medical record system EPIC, retrospective data were collected on patients seen at Johns Hopkins who received a medication of interest in a five-year period (2013-2018). Sequential criteria were used to identify the subpopulation who presented with a chief complaint of "pruritus" or diagnosis of "itching" within three months of receiving drugs. Results: We identified 9802 patients with pruritus after drug initiation and 1,085,404 patients without. A higher proportion of those with pruritus were female (70%) than those without (58%), p < 0.001. Patients in both groups were most commonly 50 to 79 years old. A higher proportion of patients with pruritus were black (40%) compared to those without (23%), p < 0.001. In this study, the highest rates of pruritus were observed with heparin (1.11%), trimethoprim-sulfamethoxazole (1.06%), and calcium channel blockers (0.92%). Psychiatric/neurologic drugs used to treat pruritus were associated with low rates of itch. Conclusions: Certain cardiovascular and antimicrobial agents are associated with increased frequencies of pruritus. This knowledge may guide providers in clinical selection of commonly used agents to minimize adverse effects associated with reduced compliance.

Mycoplasma pneumoniae infection is associated with extrapulmonary complications, including mucocutaneous eruptions. These eruptions, which have been termed either "Stevens-Johnson syndrome" or "erythema multiforme" in the literature, may differ from drug-induced Stevens-Johnson syndrome or viral-associated erythema multiforme.

Drug therapy is occasionally accompanied by an idiosyncratic severe toxicity, which occurs very rarely, but can lead to patient mortality. Methazolamide, an anti-glaucomatous agent, could cause severe skin eruptions called Stevens-Johnson syndrome/toxic epidermal necrolyis (SJS/TEN). Its precise etiology is still uncertain. In this study, the metabolism of methazolamide was investigated in immortalized human keratinocytes to reveal the possible mechanism which causes SJS/TEN.

Most of drugs could have certain mucocutaneous reactions and COVID-19 drugs are not an exception that we focused. We systematically reviewed databases until August 15, 2020 and among initial 851 articles, 30 articles entered this study (20 case reports, 4 cohorts, and 6 controlled clinical trials). The types of reactions included AGEP, morbiliform drug eruptions, vasculitis, DRESS syndrome, urticarial vasculitis, and so on. The treatments have been used before side effects occur, included: antimalarial, anti-viral, antibiotics, tocilizumab, enoxaparin and and so on. In pandemic, we found 0.004% to 4.15% of definite drug-induced mucocutaneous reactions. The interval between drug usage and the eruption varied about few hours to 1 month; tightly dependent to the type of drug and hydroxychloroqine seems to be the drug with highest mean interval. Antivirals, antimalarials, azithromycin, and tocilizumab are most responsive drugs for adverse drug reactions, but antivirals especially in combination with antimalarial drugs are in the first step. Types of skin reactions are usually morbilliform/exanthematous maculopapular rashes or urticarial eruptions, which mostly may manage by steroids during few days. In the setting of HCQ, specific reactions like AGEP should be considered. Lopinavir/ritonavir is the most prevalent used drug among antivirals with the highest skin adverse reaction; ribarivin and remdisivir also could induce cutaneous drug reactions but favipiravir has no or less adverse effects. Logically the rate of dermatologic adverse effects among anivirals may relate to their frequency of usage. Rarely, potentially life-threatening reactions may occur. Better management strategies could achieve by knowing more about drug-induced mucocutaneous presentations of COVID-19.

Viral infections have a history of abrupt and severe eruptions through the years in the form of pandemics. And yet, definitive therapies or preventive measures are not present. Herbal medicines have been a source of various antiviral compounds such as Oseltamivir, extracted using shikimic acid from star anise (Illicium verum) and Acyclovir from Carissa edulis are FDA (Food and Drug Administration) approved antiviral drugs. In this study, we dissect the anti-coronavirus infection activity of Cissampelos pareira L (Cipa) extract using an integrative approach.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening acute inflammatory vesiculobullous reactions of the skin and mucous membranes. These severe cutaneous drug reactions are known to be caused by inciting drugs and infectious agents. Previously, we have reported the association of HLA-A*02:06 and HLA-B*44:03 with cold medicine (CM)-related SJS/TEN with severe ocular complications (SOCs) in the Japanese population. However, the conventional HLA typing method (PCR-SSOP) sometimes has ambiguity in the final HLA allele determination. In this study, we performed HLA-disease association studies in CM-SJS/TEN with SOCs at 3- or 4-field level. 120 CM-SJS/TEN patients with SOCs and 817 Japanese healthy controls are HLA genotyped using the high-resolution next-generation sequencing (NGS)-based HLA typing of HLA class I genes, including HLA-A, HLA-B, and HLA-C. Among the alleles of HLA class I genes, HLA-A*02:06:01 was strongly associated with susceptibility to CM-SJS/TEN (p = 1.15 × 10-18, odds ratio = 5.46). Four other alleles (HLA-A*24:02:01, HLA-B*52:01:01, HLA-B*46:01:01, and HLA-C*12:02:02) also demonstrated significant associations. HLA haplotype analyses indicated that HLA-A*02:06:01 is primarily associated with susceptibility to CM-SJS/TEN with SOCs. Notably, there were no specific disease-causing rare variants among the high-risk HLA alleles. This study highlights the importance of higher resolution HLA typing in the study of disease susceptibility, which may help to elucidate the pathogenesis of CM-SJS/TEN with SOCs.

Background: Erythema multiforme (EM) is an acute cutaneous eruption often associated with infections and more rarely with drugs. This review aimed to evaluate the association between erythema multiforme and coronavirus disease 2019 (COVID-19). Methods: A systematic search of PubMed/MEDLINE, Scimago Scopus, and ISI/Web of Science was performed. Original articles, case series, or case reports were evaluated and selected. Results: Fourteen articles were selected, describing a total of 70 patients. EM is a cutaneous eruption rarely occurring in COVID-19 and is, in most cases, associated with a hypersensitivity reaction to the virus. In these cases, EM seems to affect patients younger than 30 years or older than 55 years. Infrequently, some drugs used in the management of COVID-19 may induce EM, especially hydroxychloroquine. The three groups of patients seem to have different clinical characteristics and courses. Conclusions: From these data, it is possible to preliminarily propose that EM or EM-like eruptions linked to COVID-19 might be divided into three types: the virus-related juvenile type (affecting patients <30-year-old), the virus-related older type (affecting patients >55 years), and the drug-induced type. The occurrence of a skin rash does not seem to be related to the severity and clinical course of COVID-19.

With advances in drug development and our understanding of the pathophysiology of skin disease, biologic medications have emerged as powerful management tools for dermatologists. While biologics have most often been used in the management of psoriasis, they are being used off-label for the management of a variety of other immune-mediated skin diseases with overlapping molecular targets. This narrative review focuses on the novel and off-label use of biologic medications for the management of hidradenitis suppurativa (HS), pyoderma gangrenosum (PG), lichen planus (LP), and seborrheic dermatitis (SD). Review of the literature revealed that IL-17, IL-23, and tumor necrosis factor (TNF) inhibitors were being used across a variety of immune-mediated skin pathologies with variable efficacy, among other targeted biologics. While biologics were generally safe in the treatment of primary immune-mediated skin disorders, paradoxical disease eruptions were noted with biologic use and were theorized to occur owing to immune dysregulation and cytokine imbalance. While numerous case reports show promise for the use of biologics in immune-mediated skin pathologies, the variable efficacy and safety reported warrants more thorough investigations of the role of these targeted medications in comprehensive disease management.

Erythroderma is characterized by erythema and scaling affecting more than 80% of the body surface area. It is potentially life-threatening, and diagnosis of the underlying disease is a challenge. Despite laboratory improvements, many cases remain idiopathic. We aimed to analyze clinical and laboratory findings of 309 erythrodermic patients to find clues to the etiologic diagnosis. We performed a prospective study at the University of São Paulo Medical School, from 2007 to 2018, with patients with acquired erythroderma. Clinical, laboratory, histology, and molecular biology data were collected. The median age at diagnosis was 57 years, with a male-to-female ratio of 2.2. Eczema was the most frequent etiology (20.7%), followed by psoriasis (16.8%), Sézary syndrome (12.3%), drug eruption (12.3%), atopic dermatitis (8.7%), and mycosis fungoides (5.5%). Other diagnoses (6.8%) included pemphigus foliaceous, paraneoplastic erythroderma, adult T-cell leukemia/lymphoma, dermatomyositis, pityriasis rubra pilaris, lichen planus, bullous pemphigoid, and leprosy. In 52 patients (16.8%), it was not possible to elucidate erythroderma etiology. Atopic dermatitis developed erythroderma at an earlier age (median 25 years; P = 0.0001). Acute onset was associated with drug reactions and atopic dermatitis (median time from erythroderma to diagnosis of 1 and 1.5 months, respectively; P = 0.0001). Higher immunoglobulin E levels were observed in atopic dermatitis (median 24,600 U/L; P = 0.0001). Histopathology was helpful and was consistent with the final diagnosis in 72.4%. Monoclonal T-cell proliferation in the skin was observed in mycosis fungoides (33.3%) and Sézary syndrome (90.9%). At the last assessment, 211 patients (69.3%) were alive with disease, 65 (21.7%) were alive without disease, and 27 (9.1%) died with active disease. Erythroderma is a challenging syndrome with a difficult diagnostic approach. Younger age and higher immunoglobulin E levels are associated with atopic dermatitis; acute onset is observed in drug eruptions and atopic dermatitis. Histopathology and molecular biology tests are essential tools in the investigation of erythroderma.

Many patients are receiving SARS-CoV-2 vaccinations, which have been associated with a variety of adverse effects. Cutaneous adverse reactions to SARS-CoV-2 vaccinations have been progressively reported, but they have not been reviewed according to their morphological clinical patterns. The objective of this review was to summarize the existing data concerning the cutaneous adverse reactions following SARS-CoV-2 vaccines and group them according to common morphological and pathogenetic patterns. We reviewed the English language literature up to 15 August 2021, using predefined keywords to identify the relevant studies evaluating cutaneous adverse reactions associated with SARS-CoV-2 vaccines. We search for recurrent morphological patterns sharing clinical signs and symptoms and physio-pathological mechanisms. Timing to onset following the first or booster dose of the vaccine, predisposing conditions, therapeutic management, and outcome were also collected. Among the dermatological manifestations associated with SARS-CoV-2 vaccinations, we distinguished: (1) new onset reactions and (2) flares of preexisting dermatoses. The most common were injection site reactions, affecting 30-70% and generally mild or moderate. Small case series or single case reports included filler reactions, exanthemas, vascular lesions, urticaria, eczematous dermatitis, autoimmune bullous reactions, and severe cutaneous adverse reactions. In addition, the exacerbation of chronic immuno-mediated dermatoses (mainly psoriasis and atopic dermatitis) and reactivations of herpes infection were reported. The cutaneous reactions were generally mild, self-limiting, and resembled common cutaneous drug eruptions and/or COVID-19 skin manifestations.

Spirodela polyrhiza (L.) SCHLEID. has been used to treat epidemic fever, dysuria, and various skin ailments, such as measles eruptions, eczema, and pruritus, in China, Japan, and Korea. In this study, the active compounds in S. polyrhiza and their target genes were identified by network-based analysis. Moreover, the study evaluated the effects of a 70% ethanolic extract of S. polyrhiza (EESP) on skin lesions, histopathological changes, inflammatory cytokines, and chemokines in mice with contact dermatitis (CD) induced by 1-fluoro-2,4-dinitrobenzene (DNFB), and examined the inhibitory effects of EESP on mitogen-activated protein kinase (MAPK) signalling pathways. In our results, 14 active compounds and 29 CD-related target genes were identified. Among them, tumour necrosis factor (TNF) and interleukin 6 (IL-6) were identified as hub genes, and luteolin and apigenin showed a strong binding affinity with TNF (<-8 kcal/mol) and IL-6 (<-6 kcal/mol). Our in vivo studies showed that topical EESP ameliorated DNFB-induced skin lesions and histopathological abnormalities, and reduced the levels of TNF-α, interferon (IFN)-ɣ, IL-6, and monocyte chemotactic protein (MCP)-1 in inflamed tissues. In conclusion, our findings suggest the potential for dermatological applications of S. polyrhiza and suggest that its anti-dermatitis action is related to the inhibition of TNF and IL-6 by luteolin and luteolin glycosides.

T cell receptors (TCR) containing Vβ20-1 have been implicated in a wide range of T cell mediated disease and allergic reactions, making it a target for understanding these. Mechanics of T cell receptors are largely unexplained by static structures available from x-ray crystallographic studies. A small number of molecular dynamic simulations have been conducted on TCR, however are currently lacking either portions of the receptor or explanations for differences between binding and non-binding TCR recognition of respective peptide-HLA. We performed molecular dynamic simulations of a TCR containing variable domain Vβ20-1, sequenced from drug responsive T cells. These were initially from a patient showing maculopapular eruptions in response to the sulfanilamide-antibiotic sulfamethoxazole (SMX). The CDR2β domain of this TCR was found to dock SMX with high affinity. Using this compound as a perturbation, overall mechanisms involved in responses mediated by this receptor were explored, showing a chemical action on the TCR free from HLA or peptide interaction. Our simulations show two completely separate modes of binding cognate peptide-HLA complexes, with an increased affinity induced by SMX bound to the Vβ20-1. Overall binding of the TCR is mediated through a primary recognition by either the variable β or α domain, and a switch in recognition within these across TCR loops contacting the peptide and HLA occurs when SMX is present in the CDR2β loop. Large binding affinity differences are induced by summed small amino acid changes primarily by SMX modifying only three critical CDR2β loop amino acid positions. These residues, TYRβ57, ASPβ64, and LYSβ65 initially hold hydrogen bonds from the CDR2β to adjacent CDR loops. Effects from SMX binding are amplified and traverse longer distances through internal TCR hydrogen bonding networks, controlling the overall TCR conformation. Thus, the CDR2β of Vβ20-1 acts as a ligand controlled switch affecting overall TCR binding affinity.