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The Journal of Dermatology Oct 2023Phospholipase D2 (PLD2), a major isoform of the PLD family, has been reported to regulate inflammatory responses. Thus far, the relevance of PLD2 in psoriasis, an...
Phospholipase D2 (PLD2), a major isoform of the PLD family, has been reported to regulate inflammatory responses. Thus far, the relevance of PLD2 in psoriasis, an inflammatory skin disease, has not been explored. In the current study, we examined PLD2 expression in the skin of psoriasis patients and the role of PLD2 in an interleukin (IL)-23-induced mouse model of psoriasiform dermatitis. Both in situ hybridization and bulk RNA sequencing showed PLD2 gene expression is significantly higher in lesional relative to non-lesional skin of psoriasis patients or the skin of healthy subjects. PLD2 expression is also enriched in residual lesions from patients on biologic therapies. Murine in vivo studies showed that PLD2 deficiency significantly reduced psoriasiform inflammation in IL-23-injected ears, as reflected by decreases in ear thickness, expression of defensin beta 4A and the S100 calcium binding protein A7A, macrophage infiltrate, and expression of CXCL10 and IL-6. However, the expression of type 17 cytokines, IL-17A and IL-17F, were not reduced. Dual knockout of PLD1 and PLD2 offered little additional protection compared to PLD2 knockout alone in the IL-23 model. In addition, pharmacological inhibition with a pan-PLD1/PLD2 inhibitor also suppressed IL-23-induced psoriasiform dermatitis. Bone-marrow-derived macrophages from wild type (WT) and PLD2 knockout (KO) mice exhibited little difference in viability and sensitivity to lipopolysaccharide and/or interferon gamma, or resiquimod (R848). PLD2 deficiency did not alter the differentiation and function of Th17 cells in an ex vivo study with splenocytes isolated from WT and PLD2 KO mice. Overall, these data suggest that PLD2 may play a role in the pathophysiology of psoriasis. Reducing macrophage infiltrate and cytokine/chemokine production might contribute to an anti-inflammatory effect observed in PLD2 knockout mice. Further studies are required to better understand the mechanisms by which PLD2 contributes to skin lesions in psoriasis patients and psoriasiform dermatitis models.
PubMed: 37455419
DOI: 10.1111/1346-8138.16899 -
Actas Dermo-sifiliograficas Jan 2024Tumor necrosis factor α (TNF) inhibitors are used to treat different inflammatory diseases. Although these biologics have an adequate safety profile, they have been... (Review)
Review
BACKGROUND
Tumor necrosis factor α (TNF) inhibitors are used to treat different inflammatory diseases. Although these biologics have an adequate safety profile, they have been associated with paradoxical reactions.
MATERIAL AND METHODS
Retrospective review of patients on TNF inhibitor therapy who developed a paradoxical skin reaction and were seen at the dermatology department of Hospital Universitari Parc Taulí in Sabadell, Spain.
RESULTS
We collected data on 30 patients under treatment with a TNF inhibitor who developed an immune-mediated skin reaction in the form of psoriasis (90%), alopecia (6.7%), or neutrophilic dermatitis (3.3%). The most common drugs involved were adalimumab (56.7%) and infliximab (40%). Psoriasiform reactions mostly manifested as generalized plaques (62.9%) or palmoplantar pustulosis (37%). Thirteen patients (43.3%) continued on the same TNF inhibitor and 12 of them (92.3%) achieved partial or complete resolution of lesions. Five patients were switched to a different TNF inhibitor, but none of them achieved complete resolution. Eight patients were switched to a biologic with a different target, and 5 of them (62.5%) achieved partial or complete resolution.
CONCLUSIONS
Paradoxical reactions during TNF inhibitor therapy do not always require a change of treatment. In our series, the addition of a topical and/or systemic treatment resolved the skin lesions in more than half of the patients, and switching to a drug with a different target was more effective. A change of strategy should be contemplated in more serious cases.
Topics: Humans; Tumor Necrosis Factor-alpha; Tumor Necrosis Factor Inhibitors; Adalimumab; Infliximab; Psoriasis; Immunologic Factors; Necrosis
PubMed: 37437689
DOI: 10.1016/j.ad.2023.06.016 -
Clinical, Cosmetic and Investigational... 2023Pretibial pruritic papular dermatitis (PPPD) is a distinctive skin disorder in response to persistent pretibial manipulation. Clinically, it manifests as multiple...
Pretibial pruritic papular dermatitis (PPPD) is a distinctive skin disorder in response to persistent pretibial manipulation. Clinically, it manifests as multiple discrete, pruritic, flesh-colored-to-erythematous papules and plaques confined to the pretibial area. The histological hallmark of PPPD comprises irregular epidermal psoriasiform hyperplasia with parakeratosis and spongiosis, dermal fibrosis, and lymphohistiocytic infiltration. Due to its rarity and underrecognition, the prevalence and standard treatment of the disease have yet to be well elucidated. Here, we present a case of PPPD in a 60-year-old female presenting with numerous pruritic, erythematous-to-brownish papules and plaques on bilateral pretibial areas for 1.5 years. The lesions were significantly improved after 1 month of additional treatment with oral pentoxifylline. In this report, we aim to raise awareness in recognizing PPPD since it manifests unique clinical, dermoscopic, and histological features, representing pretibial skin's response to chronic rubbing. In addition, we proposed a novel effective therapy for the disease using pentoxifylline.
PubMed: 37366429
DOI: 10.2147/CCID.S420726 -
Journal of Ethnopharmacology Dec 2023Liangxue Jiedu formula (LXJDF) is an effective traditional Chinese medicine (TCM) formula for treating psoriasis of blood-heat syndrome and has been used in clinics for...
Liangxue Jiedu formula improves imiquimod-induced psoriasiform dermatitis with circadian desynchrony by regulating Th17 cell differentiation based on network pharmacological analysis.
ETHNOPHARMACOLOGICAL RELEVANCE
Liangxue Jiedu formula (LXJDF) is an effective traditional Chinese medicine (TCM) formula for treating psoriasis of blood-heat syndrome and has been used in clinics for decades.
AIM OF THE STUDY
This study aimed to discover the mechanism of LXJDF in psoriasis and the circadian clock by network pharmacology and experimental studies.
MATERIALS AND METHODS
The compounds of LXJDF were obtained from the TCMSP and BATMAN-TCM databases. The genes related to psoriasis and circadian rhythm/clock were identified by the OMIM and GeneCards databases. Then, target genes were integrated by Venn and analyzed by the String, CytoNCA, DAVID (GO and KEGG) databases, and the network was constructed using Cytoscape. Mice were raised under light disturbance for fourteen days. On the eighth day, mouse dorsal skin was shaved and smeared with 62.5 mg 5% imiquimod at 8:00 (ZT0) for six successive days. Mice were randomly divided into the model, LXJDF-H (49.2 g/kg·bw), LXJDF-L (24.6 g/kg·bw), and positive drug (dexamethasone) groups. Other mice were smeared with Vaseline under the normal light cycle as the control. The drug of each group was administered at 10:00 (ZT2) and 22:00 (ZT14). The skin lesions were observed, and PASI was scored daily. HE and immunofluorescence were used to measure pathological morphology. Th17 cytokines in serum and skin were measured by flow cytometry and qPCR. Circadian clock gene and protein expression levels were determined by qPCR and Western blotting.
RESULTS
We found 34 potential targets of LXJDF in the treatment of psoriasis and circadian rhythm and confirmed their importance by topology analysis. KEGG pathway analysis revealed that the two major pathways were Th17 cell differentiation and the HIF-1 signaling pathway. At ZT2 and ZT14, LXJDF improved IMQ-induced light disturbance mouse skin lesions, including alleviating scales, erythema, and infiltration, reducing PASI, and inhibiting keratinocyte hyperproliferation and parakeratosis. LXJDF reduced IL-17A, IL-17F, TNF-α, and IL-6 in serum at ZT2 and increased IL-10 at ZT2 and ZT14. LXJDF downregulated the expression of IL-17A and IL-17F in skin. At ZT2, LXJDF significantly upregulated CLOCK and REV-ERBα expression and downregulated HIF-1α expression. At ZT14, LXJDF decreased HIF-1α and RORγt expression and significantly increased REV-ERBα expression.
CONCLUSION
LXJDF improves psoriasis dermatitis with circadian rhythm disorders by regulating Th17 cell differentiation.
Topics: Animals; Mice; Interleukin-17; Imiquimod; Skin; Psoriasis; Cell Differentiation; Dermatitis; Disease Models, Animal; Th17 Cells; Mice, Inbred BALB C
PubMed: 37331449
DOI: 10.1016/j.jep.2023.116807 -
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 Dermatology Aug 2023Adalimumab is a human monoclonal antibody against tumor necrosis factor-α that was approved in Japan for the treatment of hidradenitis suppurativa (HS), a chronic... (Observational Study)
Observational Study
Adalimumab is a human monoclonal antibody against tumor necrosis factor-α that was approved in Japan for the treatment of hidradenitis suppurativa (HS), a chronic recurrent inflammatory skin disease. We report the results of the final analysis of the postmarketing surveillance (PMS) study (ClinicalTrials.gov: NCT03894956), which evaluated the 52-week safety and efficacy of adalimumab for HS treatment in real-world clinical practice in Japan. This multicenter, prospective, open-label, observational study (March 2019 to May 2021) included patients with HS treated with subcutaneous adalimumab at doses following the package insert. The primary endpoint was safety, and the secondary endpoints were effectiveness, including HS clinical response (HiSCR), C-reactive protein (CRP), skin pain, and Dermatology Life Quality Index (DLQI). Of the 84 patients registered at 65 sites, 83 patients were included in the analyses. Adverse drug reactions (ADRs) were reported by 10 (12.0%) patients; two patients reported a serious ADR, including one patient with serious infection. Other safety events of special interest reported were liver disorder and dermatitis psoriasiform (one patient each). Almost all patients with ADRs were recovering or had recovered, except for one patient who experienced a serious ADR of liver disorder and died. At 12 weeks, 55.4% of patients achieved HiSCR; this increased to 60.5% and 62.8% at 24 and 52 weeks of adalimumab treatment, respectively. Significant reductions from baseline in CRP (P < 0.05), skin pain (P < 0.0001), and DLQI (P < 0.0001) were observed at all time points. The results from this PMS study demonstrated that long-term adalimumab treatment is well tolerated and effective in patients with HS in real-world clinical practice in Japan.
Topics: Humans; Adalimumab; Hidradenitis Suppurativa; Japan; Prospective Studies; Anti-Inflammatory Agents; Treatment Outcome; Pain; C-Reactive Protein; Severity of Illness Index
PubMed: 37264993
DOI: 10.1111/1346-8138.16835 -
Journal of Inflammation Research 2023Psoriasis is a recurring systemic disease that can be treated with biologics to some effect. However, precisely targeting inflammatory mediators may disrupt immune...
Psoriasis is a recurring systemic disease that can be treated with biologics to some effect. However, precisely targeting inflammatory mediators may disrupt immune system homeostasis and lead to new conditions. Here, we report a case of psoriasiform dermatitis (PsoD) caused by IL-17 inhibitors (IL-17i) namely secukinumab treatment for psoriasis. This case proposes an effective use of Janus kinase inhibitor (JAKi) tofacitinib to confront lesions induced by IL-17i. This is the first case report of PsoD caused by secukinumab treated with tofacitinib.
PubMed: 37228572
DOI: 10.2147/JIR.S412418 -
International Journal of Nanomedicine 2023[This corrects the article DOI: 10.2147/IJN.S165966.].
Erratum: Chitosan-Based Nanoformulated (-)-Epigallocatechin-3-Gallate (EGCG) Modulates Human Keratinocyte-Induced Responses and Alleviates Imiquimod-Induced Murine Psoriasiform Dermatitis [Erratum].
[This corrects the article DOI: 10.2147/IJN.S165966.].
PubMed: 37197027
DOI: 10.2147/IJN.S416060 -
Clinical Dysmorphology Jul 2023MSMO1 deficiency (OMIM #616834) is an ultrarare autosomal recessive disorder of distal cholesterol metabolism with only five cases reported to date. The disorder is...
MSMO1 deficiency (OMIM #616834) is an ultrarare autosomal recessive disorder of distal cholesterol metabolism with only five cases reported to date. The disorder is caused by missense variants in the MSMO1 gene encoding methylsterol monooxygenase 1, leading to the accumulation of methylsterols. Clinically, MSMO1 deficiency is characterized by growth and developmental delay, often in association with congenital cataracts, microcephaly, psoriasiform dermatitis and immune dysfunction. Treatment with oral and topical cholesterol supplements and statins was reported to improve the biochemical, immunological, and cutaneous findings, supporting a potential treatment following the precision diagnosis of MSMO1 deficiency. We describe two siblings from a consanguineous family presenting with novel clinical features of polydactyly, alopecia and spasticity. Whole-exome sequencing revealed a novel, homozygous c.548A > C, p.(Glu183Ala) variant. Based on previously published treatment algorithms, we initiated a modified dosage regime with systemic cholesterol supplementation, statins and bile acid along with topical application of a cholesterol/statin formulation. This resulted in a marked improvement of psoriasiform dermatitis and some hair growth.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Neurodevelopmental Disorders; Cholesterol; Microcephaly; Dermatitis; Alopecia; Polydactyly; Pedigree
PubMed: 37195326
DOI: 10.1097/MCD.0000000000000461 -
Journal of Dermatological Science Jun 2023Biologics against IL-17A, IL-23 and TNF-α achieve a great success in treating psoriasis. However, the majority of patients still have some residual lesions left and...
BACKGROUND
Biologics against IL-17A, IL-23 and TNF-α achieve a great success in treating psoriasis. However, the majority of patients still have some residual lesions left and require combination therapy to reach complete clearance. Topical medicine is an optional choice but only has limited categories. Besides, drug resistance is very often. Thus, topical medicine targeting new signaling pathway is still in an urgent need in the biologics era.
OBJECTIVE
To investigate the role of topical Entinostat, a selective inhibitor of histone deacetylases 1 (HDAC1) that has been tested in clinic trials to treat solid tumors and hematological malignancies, in psoriasis therapy.
METHODS
Efficacious Entinostat were tested in a mouse imiquimod (IMQ)-induced psoriasiform dermatitis (PsD) model. An in vitro model consisting of human CD4 + T cell, murine T cells and NHEKs were used to screen Entinostat for inhibition of cutaneous inflammatory genes.
RESULTS
Topical application of Entinostat significantly improved psoriasiform inflammation in imiquimod-induced mice model with great reduction of IL-17A+ γδT cell infiltration in skin. Entinostat is powerful agent in inhibition of Th17 cell generation and the expression of psoriasis-related inflammatory mediators by primary keratinocytes upon CD4 T cells stimulation.
CONCLUSION
Our findings suggest Entinostat is a promising topical medicine for psoriasis treatment.
Topics: Humans; Animals; Mice; Imiquimod; Interleukin-17; Histone Deacetylase 1; Skin; Psoriasis; Eczema; Disease Models, Animal; Mice, Inbred BALB C
PubMed: 37173222
DOI: 10.1016/j.jdermsci.2023.05.001