Search for the best biologic for psoriasis Sugaya, M.
British journal of dermatology (1951),
September 2021, 2021-09-00, 20210901, Letnik:
185, Številka:
3
Journal Article
Recenzirano
Linked Article: Tollenaere et al. Br J Dermatol 2021; 185:585–594.
Advanced-stage mycosis fungoides (MF)/Sézary syndrome (SS) patients are weighted by an unfavorable prognosis and share an unmet clinical need of effective treatments. International guidelines are ...available detailing treatment options for the different stages but without recommending treatments in any particular order due to lack of comparative trials. The aims of this second CLIC study were to retrospectively analyze the pattern of care worldwide for advanced-stage MF/SS patients, the distribution of treatments according to geographical areas (USA versus non-USA), and whether the heterogeneity of approaches has potential impact on survival.
This study included 853 patients from 21 specialist centers (14 European, 4 USA, 1 each Australian, Brazilian, and Japanese).
Heterogeneity of treatment approaches was found, with up to 24 different modalities or combinations used as first-line and 36% of patients receiving four or more treatments. Stage IIB disease was most frequently treated by total-skin-electron-beam radiotherapy, bexarotene and gemcitabine; erythrodermic and SS patients by extracorporeal photochemotherapy, and stage IVA2 by polychemotherapy. Significant differences were found between USA and non-USA centers, with bexarotene, photopheresis and histone deacetylase inhibitors most frequently prescribed for first-line treatment in USA while phototherapy, interferon, chlorambucil and gemcitabine in non-USA centers. These differences did not significantly impact on survival. However, when considering death and therapy change as competing risk events and the impact of first treatment line on both events, both monochemotherapy (SHR = 2.07) and polychemotherapy (SHR = 1.69) showed elevated relative risks.
This large multicenter retrospective study shows that there exist a large treatment heterogeneity in advanced MF/SS and differences between USA and non-USA centers but these were not related to survival, while our data reveal that chemotherapy as first treatment is associated with a higher risk of death and/or change of therapy and thus other therapeutic options should be preferable as first treatment approach.
Multiple sequential genetic and epigenetic alterations underlie cancer development and progression. Overcoming cellular senescence is an early step in cancer pathogenesis. Here, we demonstrate that a ...noncoding regulatory RNA, microRNA-16 (miR-16), has the potential to induce cellular senescence. First, we examined the expression of miR-16 in primary cutaneous T-cell lymphoma (CTCL) and other non-Hodgkin T/natural killer (NK)-cell lymphomas and found that miR-16 was downregulated than that in the corresponding normal cells. Notably, miR-16 expression was reduced as the primary CTCL progressed from the early stage to the advanced stage. Next, we transduced CTCL cells with miR-16 to examine whether this miRNA exhibited tumor-suppressive effects in CTCL cells. In CTCL cells expressing wild-type p53, forced expression of miR-16 enhanced p21 expression via downregulation of the polycomb group protein Bmi1, thereby inducing cellular senescence. Alternatively, in CTCL cells lacking functional p53, miR-16 induced compensatory apoptosis. The miR-16 transfection significantly decreased senescent cells and increased apoptotic cells in p21-knockdown CTCL cells expressing wild-type p53, suggesting that the presence or absence of p21 may be the most important condition in the senescence-apoptosis switch in CTCL lymphomagenesis. Furthermore, we found that the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) restored the expression of miR-16 and its essential targets, induced senescence in CTCL cells expressing wild-type p53 and promoted apoptosis in cells with nonfunctional p53. Moreover, we found that other T/NK-cell lymphoma cell lines showed similar tumor-suppressive effects in response to miR-16 and SAHA and that these effects were dependent on p53 status. These results suggested that epigenetic silencing of miR-16 may be a key step during lymphoma development. Elucidation of the essential targets of miR-16 and SAHA provides a basis for the clinical application of SAHA in the treatment of CTCL and other non-Hodgkin T/NK-cell lymphomas.
Summary
Background
LL‐37 is an antimicrobial peptide with pleiotropic effects on the immune system, angiogenesis and tissue remodelling. These are cardinal pathological events in systemic sclerosis ...(SSc).
Objectives
To elucidate the potential role of LL‐37 in SSc.
Methods
The expression of target molecules was evaluated by immunostaining and quantitative reverse‐transcription real‐time polymerase chain reaction in human and murine skin. The mechanisms regulating LL‐37 expression in endothelial cells were examined by gene silencing and chromatin immunoprecipitation. Serum LL‐37 levels were determined by enzyme‐linked immunosorbent assay.
Results
In SSc lesional skin, LL‐37 expression was increased in dermal fibroblasts, perivascular inflammatory cells, keratinocytes and, particularly, dermal small vessels. Expression positively correlated with interferon‐α expression, possibly reflecting LL‐37‐dependent induction of interferon‐α. In SSc animal models, bleomycin‐treated skin exhibited the expression pattern of CRAMP, a murine homologue of LL‐37, similar to that of LL‐37 in SSc lesional skin. Furthermore, Fli1+/− mice showed upregulated expression of CRAMP in dermal small vessels. Fli1 binding to the CAMP (LL‐37 gene) promoter and Fli1 deficiency‐dependent induction of LL‐37 were also confirmed in human dermal microvascular endothelial cells. In the analysis of sera, patients with SSc had serum LL‐37 levels significantly higher than in healthy controls. Furthermore, serum LL‐37 levels positively correlated with skin score and the activity of alveolitis and were significantly elevated in patients with digital ulcers compared with those without.
Conclusions
LL‐37 upregulation, induced by Fli1 deficiency at least in endothelial cells, potentially contributes to the development of skin sclerosis, interstitial lung disease and digital ulcers in SSc.
What's already known about this topic?
LL‐37, an antimicrobial peptide, has been shown to be upregulated in systemic sclerosis dermal fibroblasts.
LL‐37 potentially contributes to dermal fibrosis through its antiapoptotic effect on those cells.
What does this study add?
LL‐37 potentially contributes to the development of skin sclerosis, interstitial lung disease and digital ulcers in systemic sclerosis.
This further supports the critical role of antimicrobial peptides in the development of autoimmune and inflammatory diseases.
What is the translational message?
LL‐37 induction due to Fli1 deficiency in endothelial cells supports the notion that Fli1 deficiency is a key predisposing factor in the pathogenesis of systemic sclerosis.
This has recently been demonstrated by the establishment of a new systemic sclerosis animal model, with mice double heterozygous for the Klf5 and Fli1 genes.
Summary
Background
Endothelial protein C receptor (EPCR), expressed predominantly on endothelial cells, plays a critical role in the regulation of the coagulation system and also mediates various ...cytoprotective effects by binding and activating protein C. So far, the role of EPCR has not been studied in systemic sclerosis (SSc).
Objectives
To investigate the potential contribution of EPCR to the development of SSc.
Methods
EPCR expression was examined in skin samples and cultivated dermal microvascular endothelial cells by immunostaining, immunoblotting and/or quantitative reverse‐transcription polymerase chain reaction. Fli1, binding to the PROCR promoter, was assessed by chromatin immunoprecipitation. Serum EPCR levels were determined by enzyme‐linked immunosorbent assay in 65 patients with SSc and 20 healthy subjects.
Results
EPCR expression was decreased in dermal small vessels of SSc lesional skin compared with those of healthy control skin. Transcription factor Fli1, deficiency of which is implicated in SSc vasculopathy, occupied the PROCR promoter, and EPCR expression was suppressed in Fli1 small interfering RNA‐treated endothelial cells and dermal small vessels of Fli1+/− mice. In patients with SSc, decreased serum EPCR levels were associated with diffuse skin involvement, interstitial lung disease and digital ulcers. Furthermore, serum EPCR levels inversely correlated with plasma levels of plasmin–α2‐plasmin inhibitor complex (PIC). Importantly, bosentan significantly reversed circulating EPCR and PIC levels in patients with SSc, and the expression of Fli1 and EPCR in dermal small vessels was elevated in patients treated with bosentan compared with untreated patients.
Conclusions
Endothelial EPCR downregulation due to Fli1 deficiency may contribute to hypercoagulation status leading to tissue fibrosis and impaired peripheral circulation in SSc.
What's already known about this topic?
Endothelial protein C receptor (EPCR) plays a critical role in the coagulation system and mediates various cytoprotective effects by binding and activating protein C.
The role of EPCR has not been studied in the impaired coagulation/fibrinolysis system of systemic sclerosis.
What does this study add?
EPCR downregulation potentially contributes to the development of digital ulcers and tissue fibrosis in systemic sclerosis.
This further supports the critical role of an impaired coagulation/fibrinolysis system in this disease.
Linked Comment: Jinnin, Br J Dermatol 2016; 174: 263.
Summary
Background
Lipocalin‐2 is an adipocytokine implicated in apoptosis, innate immunity, angiogenesis, and the development of chronic kidney disease.
Objectives
To investigate the role of ...lipocalin‐2 in systemic sclerosis (SSc).
Materials and methods
Serum lipocalin‐2 levels were determined by enzyme‐linked immunosorbent assay in 50 patients with SSc and 19 healthy subjects. Lipocalin‐2 expression was evaluated in the skin of patients with SSc and bleomycin (BLM)‐treated mice and in Fli1‐deficient endothelial cells by reverse transcriptase‐real time polymerase chain reaction, immunoblotting and/or immunohistochemistry.
Results
Although serum lipocalin‐2 levels were comparable between patients with SSc and healthy controls, the prevalence of scleroderma renal crisis was significantly higher in patients with SSc with elevated serum lipocalin‐2 levels than in those with normal levels. Furthermore, serum lipocalin‐2 levels inversely correlated with estimated glomerular filtration rate in patients with SSc with renal dysfunction. Among patients with SSc with normal renal function, serum lipocalin‐2 levels positively correlated with skin score in patients with diffuse cutaneous SSc with disease duration of < 3 years and inversely correlated with estimated right ventricular systolic pressure in total patients with SSc. Importantly, in SSc lesional skin, lipocalin‐2 expression was increased in dermal fibroblasts and endothelial cells. In BLM‐treated mice, lipocalin‐2 was highly expressed in dermal fibroblasts, but not in endothelial cells. On the other hand, the deficiency of transcription factor Fli1, which is implicated in SSc vasculopathy, induced lipocalin‐2 expression in cultivated endothelial cells.
Conclusions
Lipocalin‐2 may be involved in renal dysfunction and dermal fibrosis of SSc. Dysregulated matrix metalloproteinase‐9/lipocalin‐2‐dependent angiogenesis due to Fli1 deficiency may contribute to the development of pulmonary arterial hypertension associated with SSc.
What's already known about this topic?
Adipokines have been shown to play various important roles in systemic sclerosis (SSc).
Lipocalin‐2 is a member of the adipokines, which are implicated in apoptosis, innate immunity, angiogenesis, and the development of chronic kidney disease.
What does this study add?
Lipocalin‐2 potentially contributes to the development of skin sclerosis, pulmonary arterial hypertension and renal damage in SSc, further supporting the critical roles of adipokines in the pathogenesis of this disease.
Summary
Background
Interleukin (IL)‐25 is a member of the IL‐17 family, which can promote and augment T‐helper (Th) type 2 responses. The expression of IL‐25 and its cognate receptor, IL‐25 receptor ...(IL‐25R), is upregulated and correlated with disease activity in Th2‐associated diseases.
Objectives
To examine the expression and function of IL‐25 in cutaneous T‐cell lymphoma (CTCL).
Methods
Expression and location of IL‐25 in lesional skin was investigated with immunohistochemistry. The effect of various cytokines on IL‐25 production from normal human epidermal keratinocytes was assessed by quantitative reverse‐transcription real‐time polymerase chain reaction. Serum IL‐25 levels were measured by enzyme‐linked immunosorbent assay. The direct effect of IL‐25 on tumour cells was also examined using CTCL cell lines and peripheral blood mononuclear cells in patients with Sézary syndrome.
Results
IL‐25 expression was increased in epidermal keratinocytes in lesional skin of CTCL. Th2 cytokines, IL‐4 and IL‐13, and periostin induced IL‐25 expression by normal human epidermal keratinocytes. Serum IL‐25 levels were increased in patients with advanced CTCL and correlated with serum lactate dehydrogenase levels. MyLa cells expressed IL‐25R and its expression was augmented by stimulation with IL‐25. IL‐25 enhanced IL‐13 production from MyLa cells via phosphorylation of signal transducer and activator of transcription 6. Peripheral blood mononuclear cells from one patient with Sézary syndrome expressed IL‐25R and showed increase of IL‐13 production by IL‐25.
Conclusions
Th2 cytokines highly expressed in CTCL lesional skin induce IL‐25 production by epidermal keratinocytes, which may, in turn, lead to formation of a Th2‐dominant microenvironment through the direct induction of IL‐13 by tumour cells.
What's already known about this topic?
Cutaneous T‐cell lymphomas (CTCLs), such as mycosis fungoides and Sézary syndrome, are regarded as T helper 2 (Th2)‐type diseases, and a Th2‐dominant microenvironment is beneficial for tumour cells.
Interleukin (IL)‐25 has the capacity to promote and augment Th2 responses and is associated with several Th2‐type diseases, including atopic dermatitis.
What does this study add?
Th2 cytokines highly expressed in lesional skin of CTCL induce IL‐25 production by epidermal keratinocytes.
IL‐25 directly induces IL‐13 production from CTCL tumour cells through signal transducer and activator of transcription 6 (STAT6) signalling pathways, resulting in the formation of a Th2‐dominant microenvironment.
What is the translational message?
Our results support the notion that activation of STAT6 is a key signalling pathway for the creation of a Th2‐dominant microenvironment in CTCL.
As the destruction of a Th2‐dominant microenvironment is effective for CTCL, IL‐25 and STAT6 can be a therapeutic target for CTCL.
Tumor cells in cutaneous T-cell lymphoma express limited numbers of chemokine receptors. We investigated the expression patterns of CXCR3, CCR3, CCR4 and CCR10 in mycosis fungoides, Sézary syndrome, ...lym-phomatoid papulosis and anaplastic large cell lymphoma in 121 skin biopsy samples. CXCR3 was expressed in 86% of mycosis fungoides cases but in no anaplastic large cell lymphoma cases. CCR3 was expressed in 73% of cases of CD30+ lymphoproliferative disorders such as lymphomatoid papulosis and anaplastic large cell lymphoma. Mycosis fungoides/Sézary syndrome patients with high CCR3 or CCR4 expression had a poorer survival prognosis than mycosis fungoides/Sézary syndrome patients whose tumor cells did not express these receptors. CCR10 was expressed in 50% of mycosis fungoides/Sézary syndrome cases and in 13% of cases with CD30+ lym-phoproliferative disorders. These results suggest that differential patterns of CXCR3, CCR3, CCR4 and CCR10 expression are useful for the diagnosis of cutaneous T-cell lymphoma. Moreover, expression of CCR3 or CCR4 suggests a poor prognosis in mycosis fungoides/Sézary syndrome.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Summary
Background
Interleukin (IL)‐33 is a recently identified cytokine, which is a member of the IL‐1 family and binds to a heterodimeric receptor comprising ST2 (suppression of tumorigenicity 2) ...and IL‐1 receptor accessory protein. Serum levels of IL‐33 have been reported to be upregulated in various T helper (Th)1/Th17‐mediated diseases, such as rheumatoid arthritis and inflammatory bowel disease. IL‐33 expression is increased in lesional skin in patients with psoriasis, but serum levels in patients with psoriasis have not yet been studied.
Aim
To study serum IL‐33 levels in patients with psoriasis, a Th1/Th17‐mediated skin disease, before and after anti‐tumour necrosis factor (TNF)‐α therapy.
Methods
Serum IL‐33 levels were measured in patients with psoriasis vulgaris (PV), psoriatic arthritis (PsA) or pustular psoriasis (PP), and compared with those of healthy controls. Associations between serum IL‐33 levels and serum TNF‐α, IL‐6, vascular endothelial growth factor and C‐reactive protein levels were also studied. In addition, the effect of IL‐33 stimulation on IL‐6, IL‐8, TNF‐α and VEGF secretion by human keratinocyte was analysed.
Results
Serum IL‐33 levels in patients with PV, PsA and PP were significantly higher than those in healthy controls. Serum IL‐33 levels correlated with serum TNF‐α levels in patients with psoriasis, and decreased after anti‐TNF‐α therapy. IL‐33 stimulated IL‐6 and IL‐8 secretion by human keratinocytes.
Conclusions
These results suggest that serum IL‐33 levels generally reflect increased inflammation in patients with psoriasis.
PDF
