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Journal of the American Academy of... Nov 2020Immune checkpoint inhibitors have emerged as a pillar in the management of advanced malignancies. However, nonspecific immune activation may lead to immune-related... (Review)
Review
Immune checkpoint inhibitors have emerged as a pillar in the management of advanced malignancies. However, nonspecific immune activation may lead to immune-related adverse events, wherein the skin and its appendages are the most frequent targets. Cutaneous immune-related adverse events include a diverse group of inflammatory reactions, with maculopapular rash, pruritus, psoriasiform and lichenoid eruptions being the most prevalent subtypes. Cutaneous immune-related adverse events occur early, with maculopapular rash presenting within the first 6 weeks after the initial immune checkpoint inhibitor dose. Management involves the use of topical corticosteroids for mild to moderate (grades 1-2) rash, addition of systemic corticosteroids for severe (grade 3) rash, and discontinuation of immunotherapy with grade 4 rash. Bullous pemphigoid eruptions, vitiligo-like skin hypopigmentation/depigmentation, and psoriasiform rash are more often attributed to programmed cell death-1/programmed cell death ligand-1 inhibitors. The treatment of bullous pemphigoid eruptions is similar to the treatment of maculopapular rash and lichenoid eruptions, with the addition of rituximab in grade 3-4 rash. Skin hypopigmentation/depigmentation does not require specific dermatologic treatment aside from photoprotective measures. In addition to topical corticosteroids, psoriasiform rash may be managed with vitamin D analogues, narrowband ultraviolet B light phototherapy, retinoids, or immunomodulatory biologic agents. Stevens-Johnson syndrome and other severe cutaneous immune-related adverse events, although rare, have also been associated with checkpoint blockade and require inpatient care as well as urgent dermatology consultation.
Topics: Drug Eruptions; Humans; Immune Checkpoint Inhibitors; Neoplasms
PubMed: 32454097
DOI: 10.1016/j.jaad.2020.03.132 -
Dermatology (Basel, Switzerland) 2023Dupilumab is the first approved IL-4Rα inhibitor for the treatment of atopic dermatitis at present with good efficacy and safety. However, there have been several... (Review)
Review
BACKGROUND
Dupilumab is the first approved IL-4Rα inhibitor for the treatment of atopic dermatitis at present with good efficacy and safety. However, there have been several reports of psoriasis and psoriasiform manifestations occurring after dupilumab therapy in recent years, showing a new paradoxical cutaneous reaction associated with biologics.
SUMMARY
This is a scoping review in order to summarize the demographics and epidemiology, clinical manifestations, diagnosis, potential pathogenesis, and promising management of dupilumab-associated psoriasis and psoriasiform manifestations.
Topics: Humans; Antibodies, Monoclonal, Humanized; Dermatitis, Atopic; Psoriasis; Interleukin-4; Interleukin Inhibitors; Treatment Outcome
PubMed: 37100035
DOI: 10.1159/000530608 -
Cell Death & Disease Oct 2021Psoriasis is a common, chronic, and recurrent inflammatory disease. It is characterized by hyperproliferation and abnormal differentiation of keratinocytes. Keratinocyte...
Psoriasis is a common, chronic, and recurrent inflammatory disease. It is characterized by hyperproliferation and abnormal differentiation of keratinocytes. Keratinocyte death is also involved in many pathophysiological conditions and amplifies the inflammatory cascade. As a newly recognized form of cell death, ferroptosis is involved in several inflammatory diseases. In this study, we aimed to investigate a previously unrecognized role for ferroptosis in psoriasis. Ferroptosis is mediated by lipid peroxidation and iron overload. Compared with normal lesions, the mRNA expression of acyl-CoA synthetase long-chain family member 4 (ACSL4), prostaglandin-endoperoxide synthase 2 (PTGS2), and transferrin receptor (TFRC) were highly expressed in psoriatic lesions, with decreased levels of glutathione peroxidase 4 (GPX4), ferritin light chain (FTL), and ferritin heavy chain 1 (FTH1). The protein levels of ACSL4 and GPX4 were consistent with their mRNA levels. A similar tendency of ferroptosis was also observed in erastin-treated human primary keratinocytes and the Imiquimod (IMQ)-induced model of psoriasis. To investigate the correlation between inflammation and peroxidation, we analyzed single-cell RNA-sequencing data and identified 15 cell types. There was a high correlation between the activity of the lipid oxidation and the Th22/Th17 response in keratinocytes at a single-cell level. Moreover, ferrostatin-1 (Fer-1), a potent inhibitor of lipid peroxidation, suppressed ferroptosis-related changes in erastin-treated keratinocytes and alleviated psoriasiform dermatitis of IMQ-induced models. Additionally, Fer-1 blocked inflammatory responses in vitro and in vivo, reducing the production of cytokines including TNF-α, IL-6, IL-1α, IL-1β, IL-17, IL-22, and IL-23. This study revealed an expression pattern of ferroptosis in which specific molecules enhance inflammatory reactions in psoriasis.
Topics: Animals; Case-Control Studies; Ferroptosis; Humans; Inflammation; Keratinocytes; Mice; Psoriasis
PubMed: 34707088
DOI: 10.1038/s41419-021-04284-5 -
Journal of the American Academy of... Oct 2021Immune checkpoint inhibitors (ICIs) have emerged as active therapies for a variety of cancers. Cutaneous toxicities are common immune-related adverse events and patients... (Review)
Review
IMPORTANCE
Immune checkpoint inhibitors (ICIs) have emerged as active therapies for a variety of cancers. Cutaneous toxicities are common immune-related adverse events and patients will often be referred to dermatologists for evaluation.
OBSERVATIONS
Cutaneous adverse events to ICIs can have a variety of clinical presentations. Among the more common are eczematous, morbilliform, and lichenoid dermatoses, as well as vitiligo and pruritus. Less common adverse events include psoriasiform dermatoses, bullous disorders, and severe cutaneous adverse reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms. Because of the immunologic mechanism of ICIs, there are also a variety of rheumatologic adverse reactions with cutaneous manifestations, such as scleroderma, dermatomyositis, cutaneous lupus erythematosus, and various vasculitides. These cutaneous reactions often respond to topical or systemic steroids, although specific toxicities may have alternative treatments available.
CONCLUSIONS AND RELEVANCE
As they become more widely prescribed, dermatologists will see an increasing number of patients with cutaneous adverse events caused by ICI therapies. Accurately diagnosing and treating these toxicities is paramount to achieving the most favorable outcomes for patients.
Topics: Humans; Immune Checkpoint Inhibitors; Immunotherapy; Skin; Stevens-Johnson Syndrome; Vitiligo
PubMed: 34332798
DOI: 10.1016/j.jaad.2020.09.054 -
Frontiers in Immunology 2023Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block key mediators of tumor-mediated immune evasion. The frequency of its use has increased rapidly... (Review)
Review
Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block key mediators of tumor-mediated immune evasion. The frequency of its use has increased rapidly and has extended to numerous cancers. ICIs target immune checkpoint molecules, such as programmed cell death protein 1 (PD-1), PD ligand 1 (PD-L1), and T cell activation, including cytotoxic T-lymphocyte-associated protein-4 (CTLA-4). However, ICI-driven alterations in the immune system can induce various immune-related adverse events (irAEs) that affect multiple organs. Among these, cutaneous irAEs are the most common and often the first to develop. Skin manifestations are characterized by a wide range of phenotypes, including maculopapular rash, psoriasiform eruption, lichen planus-like eruption, pruritus, vitiligo-like depigmentation, bullous diseases, alopecia, and Stevens-Johnson syndrome/toxic epidermal necrolysis. In terms of pathogenesis, the mechanism of cutaneous irAEs remains unclear. Still, several hypotheses have been proposed, including activation of T cells against common antigens in normal tissues and tumor cells, increased release of proinflammatory cytokines associated with immune-related effects in specific tissues/organs, association with specific human leukocyte antigen variants and organ-specific irAEs, and acceleration of concurrent medication-induced drug eruptions. Based on recent literature, this review provides an overview of each ICI-induced skin manifestation and epidemiology and focuses on the mechanisms underlying cutaneous irAEs.
Topics: Humans; Immune Checkpoint Inhibitors; Antineoplastic Agents, Immunological; Immunotherapy; Neoplasms; Drug Eruptions
PubMed: 36891313
DOI: 10.3389/fimmu.2023.1071983 -
Biologics-Induced Immunophenotypic Cross-Switching in Patients with Psoriasis and Atopic Dermatitis.Indian Journal of Dermatology 2023Antibody-based therapies that inhibit pro-inflammatory cytokine signalling are commonly used in dermatology. Paradoxically, these biological agents may induce or... (Review)
Review
Antibody-based therapies that inhibit pro-inflammatory cytokine signalling are commonly used in dermatology. Paradoxically, these biological agents may induce or exacerbate paradoxical reactions. Recently, it has been reported that the treatment of eczema with dupilumab can lead to the development of psoriasiform eruptions, which we called psoriasiform paradoxical reactions (P-PRs). Conversely, cases of eczematous paradoxical reactions (E-PRs) have also been described in patients with psoriasis treated with biologics. To summarise the case characteristics and disease features of phenotypic transition between psoriasis and eczematoid dermatitis, and to explore the mechanism or connection related to biological agents or patients' genetic characteristics, a systematic review was conducted for P-PRs in atopic dermatitis and E-PRs in patients with psoriasis treated with corresponding biological agents, respectively. We identified a series of P-PRs in 42 atopic dermatitis cases treated with dupilumab. The time to onset of P-PRs typically ranged from weeks to months, with a mean latency period of 22.65 weeks. Almost all patients presented with new-onset P-PRs. Simultaneously, we reviewed 22 articles reporting 51 patients with psoriasis with biological agent-induced E-PRs, which occurred on average at 24.47 weeks, 72.55% of them induced by IL-17A inhibitors. 48.98% (24/49) of cases reported a positive personal history of atopy, which may suggest an increased risk of biological agent-induced paradoxical eruptions. Overall, the improvement or resolution upon discontinuation of the inciting biologics was relatively common, and further studies are needed to estimate the real prevalence and unveil the pathophysiological mechanisms of these paradoxical events.
PubMed: 37275804
DOI: 10.4103/ijd.ijd_871_22 -
The Journal of Allergy and Clinical... May 2023Psoriasis is a chronically relapsing inflammatory skin disease primarily perpetuated by skin-resident IL-17-producing T (T17) cells. Pellino-1 (Peli1) belongs to a...
BACKGROUND
Psoriasis is a chronically relapsing inflammatory skin disease primarily perpetuated by skin-resident IL-17-producing T (T17) cells. Pellino-1 (Peli1) belongs to a member of E3 ubiquitin ligase mediating immune receptor signaling cascades, including nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) pathway.
OBJECTIVE
We explored the potential role of Peli1 in psoriatic inflammation in the context of skin-resident T17 cells.
METHODS
We performed single-cell RNA sequencing of relapsing and resolved psoriatic lesions with analysis for validation data set of psoriasis. Mice with systemic and conditional depletion of Peli1 were generated to evaluate the role of Peli1 in imiquimod-induced psoriasiform dermatitis. Pharmacologic inhibition of Peli1 in human CD4 T cells and ex vivo human skin cultures was also examined to evaluate its potential therapeutic implications.
RESULTS
Single-cell RNA sequencing analysis revealed distinct T-cell subsets in relapsing psoriasis exhibiting highly enriched gene signatures for (1) tissue-resident T cells, (2) T17 cells, and (3) NF-κB signaling pathway including PELI1. Peli1-deficient mice were profoundly protected from psoriasiform dermatitis, with reduced IL-17A production and NF-κB activation in γδ T17 cells. Mice with conditional depletion of Peli1 treated with FTY720 revealed that Peli1 was intrinsically required for the skin-resident T17 cell immune responses. Notably, pharmacologic inhibition of Peli1 significantly ameliorated murine psoriasiform dermatitis and IL-17A production from the stimulated human CD4 T cells and ex vivo skin explants modeling psoriasis.
CONCLUSION
Targeting Peli1 would be a promising therapeutic strategy for psoriasis by limiting skin-resident T17 cell immune responses.
Topics: Mice; Humans; Animals; Interleukin-17; NF-kappa B; Psoriasis; Skin; Dermatitis; Disease Models, Animal; Nuclear Proteins; Ubiquitin-Protein Ligases
PubMed: 36646143
DOI: 10.1016/j.jaci.2022.12.823 -
The Annals of Pharmacotherapy Apr 2024
PubMed: 38590149
DOI: 10.1177/10600280241244511 -
Frontiers in Allergy 2023Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. Since the approval of ipilimumab in 2011, a total of nine ICIs have gained indications for... (Review)
Review
Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. Since the approval of ipilimumab in 2011, a total of nine ICIs have gained indications for various solid and hematologic malignancies. The expanding use of ICIs in oncology underscores the need for diagnosis and treatment expertise in immune related adverse events (irAE). Cutaneous toxicities are the earliest and most common irAE in this class of therapy. In addition to the more frequent reactions including vitiligo, lichenoid dermatitis, psoriasiform dermatitis, other less common skin toxicities including bullous dermatoses, neutrophilic dermatoses, and autoimmune dermato-rheumatologic diseases have been reported. Even though less than 3% of cutaneous irAEs (irCAEs) are classified as grade 3 or higher events, irCAEs can greatly impact quality of life. Appropriate management of irCAEs is critical to avoid unwarranted interruptions or discontinuation of lifesaving immunotherapy.
PubMed: 36938327
DOI: 10.3389/falgy.2023.1147513