Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
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This achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
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We are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
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Thank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
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\n'}],latestNews:[{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"},{slug:"intechopen-identified-as-one-of-the-most-significant-contributor-to-oa-book-growth-in-doab-20210809",title:"IntechOpen Identified as One of the Most Significant Contributors to OA Book Growth in DOAB"}]},book:{item:{type:"book",id:"11032",leadTitle:null,fullTitle:"Bats - Disease-Prone but Beneficial",title:"Bats",subtitle:"Disease-Prone but Beneficial",reviewType:"peer-reviewed",abstract:"Bats are widely distributed and vary enormously in their ecology, sociality, and behavior. They offer diverse cultural and economic contributions to human populations, such as ecotourism, guano, medicinal products, religious significance, and vector control, to name a few. Insectivorous bats consume massive quantities of insects and other arthropods, controlling important agricultural pests and potential disease vectors. Bats feeding on nectar help to maintain diversity in forests through the dispersal of seeds and pollen, essential to many plant species with high economic, biological, and cultural value. At the same time, bats are often associated with zoonotic disease risks, a trend that has been magnified by the global COVID-19 pandemic, although no direct infection from bat to human has been demonstrated. Rapid deforestation is also a major contributing factor to new viral emergences. This book suggests that education is a suitable tool to minimize prejudice against bats and a key step to creating a harmonious coexistence between humans and bats. Chapters address such topics as bats in folklore and culture, bat dispersal patterns, bats in ecosystem management, pesticide exposure risks, roost-tier preference, diversity and conservation, and ecology of white-nose syndrome.",isbn:"978-1-80355-013-8",printIsbn:"978-1-80355-012-1",pdfIsbn:"978-1-80355-014-5",doi:"10.5772/intechopen.95729",price:119,priceEur:129,priceUsd:155,slug:"bats-disease-prone-but-beneficial",numberOfPages:150,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"b3d66958de87140d077b4df2f248b77d",bookSignature:"Heimo Mikkola",publishedDate:"April 20th 2022",coverURL:"https://cdn.intechopen.com/books/images_new/11032.jpg",numberOfDownloads:737,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:0,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"June 11th 2021",dateEndSecondStepPublish:"July 9th 2021",dateEndThirdStepPublish:"September 7th 2021",dateEndFourthStepPublish:"November 26th 2021",dateEndFifthStepPublish:"January 25th 2022",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"144330",title:"Dr.",name:"Heimo",middleName:"Juhani",surname:"Mikkola",slug:"heimo-mikkola",fullName:"Heimo Mikkola",profilePictureURL:"https://mts.intechopen.com/storage/users/144330/images/system/144330.png",biography:"Heimo Mikkola obtained a Ph.D. from the University of Kuopio (now Eastern Finland University), where he also served as an adjunct professor in Applied Zoology. From 1974 to 2007, he worked with the Food and Agriculture Organization (FAO) of the United Nations, first in Colombia and then in Africa, where he served as the organization’s resident representative. After retiring from the FAO in Uruguay, Dr. Mikkola has worked as a part-time professor at three Kazakh universities and one Kyrgyz university. His work has taken him to 137 countries, and he has written almost 700 reports and scientific papers and books, mainly on owls and other birds, fish, insects, and food. He has studied bats for many years on almost all continents as they often share night-time activity and biotopes with owls. This is the second book on bats he has edited for IntechOpen.",institutionString:"University of Eastern Finland",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"10",totalChapterViews:"0",totalEditedBooks:"9",institution:{name:"University of Eastern Finland",institutionURL:null,country:{name:"Finland"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"31",title:"Animal Biology",slug:"animal-biology"}],chapters:[{id:"80107",title:"Bats in Folklore and Culture: A Review of Historical Perceptions around the World",doi:"10.5772/intechopen.102368",slug:"bats-in-folklore-and-culture-a-review-of-historical-perceptions-around-the-world",totalDownloads:97,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"Belief systems of people have always been closely related to animals, which are symbolized in traditional narratives. Sociocultural definitions of animals as “good or evil” have persisted throughout the history of human beings. In the West, bats are often perceived as evil spirits, Vampires, and harbingers of death, while some cultures across the Asia-Pacific region associate bats with good fortune. Here, we review documented narratives and surveys from around the world and our ethnographic observations from Europe to analyze beliefs associated with bats. We explore the role that bats play in traditional narratives and the likely reasons for their salience, including their connections with the extraordinary and supernatural. Finally, we discuss shortly the need of education to change attitudes toward bats. In North America, education has had some effect as more people have started to understand how useful bats truly are and how few cases of bat-born rabies transmission to humans there have been in the United States and Canada. It remains to be seen, however, how effectively the further education efforts could halt or even reverse the decline of the bats around the world. It is also noted that bat tourism has a potential to conserve bat populations while providing social and economic benefits to local people in host communities.",signatures:"Alan Sieradzki and Heimo Mikkola",downloadPdfUrl:"/chapter/pdf-download/80107",previewPdfUrl:"/chapter/pdf-preview/80107",authors:[{id:"144330",title:"Dr.",name:"Heimo",surname:"Mikkola",slug:"heimo-mikkola",fullName:"Heimo Mikkola"},{id:"313892",title:"Dr.",name:"Alan",surname:"Sieradzki",slug:"alan-sieradzki",fullName:"Alan Sieradzki"}],corrections:null},{id:"79317",title:"Pesticide Exposure Risks to Chiropteran Species and the Impacts on Emerging Zoonotic Diseases",doi:"10.5772/intechopen.100643",slug:"pesticide-exposure-risks-to-chiropteran-species-and-the-impacts-on-emerging-zoonotic-diseases",totalDownloads:111,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Neonicotinoids have been in the spotlight in the pollinator community as they persist in the soil, have high water solubility, and have been associated with negative health implications on insect pollinators. The risk of new novel pesticides, including neonicotinoids, to bats are largely unknown. Bats have unique physiology as they are the only mammals capable of true and sustained flight, and have physiological adaptations including echolocation and torpor which under current protocols for acute and chronic toxicity studies in birds and terrestrial animals are not assessed. Due to these characteristics, some have argued that bats may serve as important bioindicators for ecosystem health and pesticide use. This chapter will focus on pesticides, and discuss the increased risk of exposure, morbidity, and mortality of bats species due to their unique physiology and natural life history. Special emphasis will be on potential increased risk of zoonotic disease transmission in bats exposed to emerging contaminants that suppress their immune system or cause increased biological stress.",signatures:"Sarah Hooper and Sybill Amelon",downloadPdfUrl:"/chapter/pdf-download/79317",previewPdfUrl:"/chapter/pdf-preview/79317",authors:[{id:"424746",title:"Assistant Prof.",name:"Sarah",surname:"Hooper",slug:"sarah-hooper",fullName:"Sarah Hooper"},{id:"426441",title:"Prof.",name:"Sybill",surname:"Amelon",slug:"sybill-amelon",fullName:"Sybill Amelon"}],corrections:null},{id:"78750",title:"The Physiological Ecology of White-Nose Syndrome (WNS) in North American Bats",doi:"10.5772/intechopen.100369",slug:"the-physiological-ecology-of-white-nose-syndrome-wns-in-north-american-bats",totalDownloads:70,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"White-nose Syndrome (WNS) is an emergent mycosis in North America that is caused by a severe cutaneous infection with the fungus Pseudogymnoascus destructans (Pd) during hibernation. Pseudogymnoascus destructans (Pd) was first observed in North America at a single site during the winter of 2006–2007 and has since spread to 39 U.S. States and 7 Canadian provinces. This fungus was introduced to North America from Europe, where it is endemic. WNS has thus far been observed to occur only in hibernating bats and has caused the populations of 4 North American bat species to decline by more than 84% within 7 years. Field studies have revealed that 4 other North American bat species are not afflicted with WNS when hibernating in areas where Pd occurs. The physiological and biochemical adaptations that permit some bat species to resist Pd infections are starting to be elucidated but are still poorly understood. A total of 47 different bat species are found in North America, about half of which hibernate during the winter. The potential future effects of WNS on 13 of these hibernating bat species remains to be determined.",signatures:"Craig L. Frank",downloadPdfUrl:"/chapter/pdf-download/78750",previewPdfUrl:"/chapter/pdf-preview/78750",authors:[{id:"423579",title:"Dr.",name:"Craig L.",surname:"Frank",slug:"craig-l.-frank",fullName:"Craig L. Frank"}],corrections:[{id:"79672",title:"Corrigendum: The Physiological Ecology of White-Nose Syndrome (WNS) in North American Bats",doi:null,slug:"corrigendum-the-physiological-ecology-of-white-nose-syndrome-wns-in-north-american-bats",totalDownloads:null,totalCrossrefCites:null,correctionPdfUrl:null}]},{id:"79802",title:"Bats and Ecosystem Management",doi:"10.5772/intechopen.101600",slug:"bats-and-ecosystem-management",totalDownloads:114,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Bats are among the most misperceived and undervalued animals on the planet. For wildlife ecologists, they are wonderful and incredibly fascinating creatures, but people’s feelings about bats are often negative, perhaps because bats are so mysterious. Unfortunately, these fears and myths about bats threaten conservation, biodiversity, and the entire ecosystem. Bats are among the most diverse and geographically dispersed group of living mammals. They contribute to several ecosystem services and act as biological pest crop control agents. Their abundance may reflect changes in populations of arthropod prey species. Also, bats have significant potentials as bioindicators that demonstrate measurable responses to climate change and habitat loss and that induce large-scale impacts on the biota. Indeed, bat conservation is fundamental not only for biodiversity, but also because these flying mammals provide essential ecological and economic services to humans.",signatures:"Kareem M. Soliman and Wiame W. Emam",downloadPdfUrl:"/chapter/pdf-download/79802",previewPdfUrl:"/chapter/pdf-preview/79802",authors:[{id:"424622",title:"Dr.",name:"Kareem M.",surname:"Soliman",slug:"kareem-m.-soliman",fullName:"Kareem M. Soliman"},{id:"425404",title:"Dr.",name:"Wiame W.",surname:"Emam",slug:"wiame-w.-emam",fullName:"Wiame W. Emam"}],corrections:null},{id:"78873",title:"Diversity and Conservation of Bats in Jordan",doi:"10.5772/intechopen.100407",slug:"diversity-and-conservation-of-bats-in-jordan",totalDownloads:134,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"The diversity and the conservation status of bats in Jordan are discussed based on recent studies. The bat fauna of Jordan consists of 26 bat species belonging to nine families (Emballonuridae, Hipposideridae, Pteropodidae, Miniopteridae, Molossidae, Nycteridae, Rhinolophidae, Rhinopomatidae, and Vespertilionidae). Bat echolocation calls for some selected species are included. Conservation status based on regional assessment according to the IUCN standards is amended, along with the current legislative laws for the conservation of bats. Threats affecting the bats of Jordan are highlighted including the recent introduction of wind farms and other mining activities. In addition, the role of bats in disease transmission is included.",signatures:"Zuhair S. Amr, Omar A. Abed and Mohammad Abu Baker",downloadPdfUrl:"/chapter/pdf-download/78873",previewPdfUrl:"/chapter/pdf-preview/78873",authors:[{id:"426364",title:"Prof.",name:"Zuhair S.",surname:"Amr",slug:"zuhair-s.-amr",fullName:"Zuhair S. Amr"},{id:"435738",title:"Dr.",name:"Mohammad",surname:"Abu Baker",slug:"mohammad-abu-baker",fullName:"Mohammad Abu Baker"},{id:"435739",title:"Mr.",name:"Omar A.",surname:"Abed",slug:"omar-a.-abed",fullName:"Omar A. Abed"}],corrections:null},{id:"78887",title:"Dispersal Patterns, Mating Strategy and Genetic Diversity in the Short Nosed Fruit Bat Cynopterus sphinx (Chiroptera: Pteropodidae) in Southern India",doi:"10.5772/intechopen.100496",slug:"dispersal-patterns-mating-strategy-and-genetic-diversity-in-the-short-nosed-fruit-bat-em-cynopterus-",totalDownloads:140,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The short-nosed fruit bat, Cynopterus sphinx is a common plant-visiting bat that is widely distributed throughout the Indo-Malayan region. In this chapter, we discuss the dispersal patterns, mating strategy and genetic diversity in the short-nosed fruit bat C. sphinx. We used a broad-range of techniques, including mark-recapture, radio-telemetry and molecular biology analyses. Our studies uncovered unique aspects of the dispersal, mating system and genetic diversity of these bats. Both the sexes of C. sphinx were found to disperse completely from the natal harems before subadult stage and young female C. sphinx become members of a harem much earlier than their male counterparts. The nonharem males are reproductively active, gain access to harem females and sire more offspring in July–August breeding season than March–April breeding season and presumably obtain some reproductive success. Our molecular study shows that considerable genetic diversity was observed in this species from different zonal populations, possibly due to complete dispersal of juveniles of both the sexes from their natal groups and gene flow between the zones. All these studies suggest not only a predictive framework for future studies, but also the use of these data in the management and meaningful conservation of this species.",signatures:"Thangavel Karuppudurai and Steffi Christiane Ramesh",downloadPdfUrl:"/chapter/pdf-download/78887",previewPdfUrl:"/chapter/pdf-preview/78887",authors:[{id:"423490",title:"Assistant Prof.",name:"Thangavel",surname:"Karuppudurai",slug:"thangavel-karuppudurai",fullName:"Thangavel Karuppudurai"},{id:"424795",title:"Ms.",name:"Steffi Christiane",surname:"Ramesh",slug:"steffi-christiane-ramesh",fullName:"Steffi Christiane Ramesh"}],corrections:null},{id:"77884",title:"Roost-Tier Preference in Roost-Trees: A Case Study in the Bats Pteropus giganteus",doi:"10.5772/intechopen.99450",slug:"roost-tier-preference-in-roost-trees-a-case-study-in-the-bats-em-pteropus-giganteus-em-",totalDownloads:71,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"The Indian flying foxes Pteropus giganteus are habituated to spend the day hours roosting in suitable roost trees. They are seen hanging here and there in a roost tree. It is not known whether they have preferred roost sites rather hanging spots in the concerned roost tree. To testify the said hypothesis we selected two roost trees, Albizia lebbeck and Tamarindus indica locating at distant places (75 km apart) in the arid zone of West Bengal, India during the period of last ten years. It is revealed that P. giganteus preferred branches of the roost tree which are locating in the mid-tier of tree. But depending upon the situations the less preferred sites are not spared as these sites are used by the late comers. Statistical tests following application of one-way ANOVA justified significant effect of the roost branch on the abundance of bat population (P<0.05), abundance of bats in the roost branches is highly correlated in respect to the study years (r=0.96) is also justified from the study of normality distribution plot, and the results of GLMM strongly support the hypothesis irrespective of the variables, that is branches of the roost tree and the year of observations (P = 0.0).",signatures:"Susanta Mallick, Asif Hossain and Srimanta Kumar Raut",downloadPdfUrl:"/chapter/pdf-download/77884",previewPdfUrl:"/chapter/pdf-preview/77884",authors:[{id:"350977",title:"Dr.",name:"Asif",surname:"Hossain",slug:"asif-hossain",fullName:"Asif Hossain"},{id:"426630",title:"Dr.",name:"Srimanta",surname:"Kumar Raut",slug:"srimanta-kumar-raut",fullName:"Srimanta Kumar Raut"},{id:"426637",title:"Dr.",name:"Susanta",surname:"Mallick",slug:"susanta-mallick",fullName:"Susanta 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1. Introduction
Hysteroscopy represents the endoscopic gynaecological examination of the endometrial cavity and denotes one of the most frequent investigations in gynaecology today, used in the diagnostic work up of abnormal uterine bleeding, postmenopausal bleeding and subfertility. The National Institute for Health and Care Excellence recommends an enhanced role of outpatient hysteroscopy in the diagnostic workup of heavy menstrual bleeding, leading to increase in the number of hysteroscopies being performed each year [1, 2]. Abnormal uterine bleeding in both the premenopausal and postmenopausal women is the commonest indication for diagnostic hysteroscopy. Similarly endometrial polyp is the most frequent preoperative indication for operative hysteroscopy followed by submucosal leiomyoma [3]. In a retrospective clinical study of 397 patients, dilatation and curettage failed to identify pathology in 62.5% cases subsequently found at hysterectomy within 2 months [4]. A large clinical observational study demonstrated that up to 3.7 cm pathology could be safely treated by office hysteroscopy without anaesthesia [5]. Paracervical block is however commonly used for operative hysteroscopy where cervical dilatation is required [6].
During hysteroscopy it is recommended to provide the patient with emotional support (“local-vocal”), by chatting to her and offering her to look at the monitor while explaining the findings to her in order to avoid feeling of exclusion. Dedicated nursing and healthcare assistant staff is crucial in ambulatory setting. It is recommended for patients to take 400 mg of ibuprofen or another NSAID approximately 1 hour before the procedure.
2. Vaginoscopy
The traditional approach to hysteroscopy is by utilising a vaginal speculum with or without manipulation of the cervix.
Vaginoscopy refers to a method where the hysteroscope is guided into the uterus without having to use the potentially painful vaginal instruments. The availability of miniature hysteroscopes has facilitated this development. A randomised controlled multicentre trial in the UK concluded that vaginoscopy is quicker to perform, less painful, and more successful than standard hysteroscopy and therefore should be regarded as the technique of choice for outpatient hysteroscopy [7, 8].
3. Outpatient diagnostic hysteroscopy
3.1 Abnormal uterine bleeding (AUB) in women of reproductive age group
The hysteroscopy has been gold standard in the examination of the endometrial cavity in ladies with abnormal uterine bleeding for several years. In the UK, the national best practice recommendation is that all gynaecology departments should offer dedicated outpatient hysteroscopy facility to support the diagnosis and treatment of ladies with abnormal uterine bleeding. The advances in outpatient hysteroscopy have further powered the use of this facility, and it is not required any more to put patients through general anaesthesia for this purpose [9]. In most women, the diagnosis for abnormal uterine bleeding can be made in the outpatient clinic with one-stop approach with a host of other investigations, including blood tests, pelvic ultrasound, outpatient hysteroscopy and endometrial biopsy. The prompt diagnosis permits timely treatment, avoiding unnecessary delays and patient anxiety [10].
A large number of women presenting with AUB belong to the reproductive age group. The causative factors may be structural abnormalities such as endometrial polyps or fibroids or ovulatory dysfunction and primary disorder of endometrium as described in the PALM-COEIN classification (Figure 1). These abnormalities can be readily diagnosed in outpatient setting by ambulatory hysteroscopy with or without endometrial biopsy [11, 12, 13]. Figure 2 shows office hysteroscope with different channels for diagnosis as well as removal of pathology.
Figure 1.
FIGO classification of PALM-COEIN system. Abbreviation: FIGO, International Federation of Gynaecology and Obstetrics.
Figure 2.
Omni-myosure (HOLOGIC).
3.2 Perimenopausal bleeding
For women in this age group presenting with new onset abnormal uterine bleeding, organic pathology, such as atypical hyperplasia or endometrial cancer, must be ruled out as anovulatory cycles and sinister pathology can coexist, in this cohort of women (Figure 3).
Endorsed pelvic ultrasound scan as the first-line tool for identifying structural abnormalities. Hysteroscopy remains the gold standard for precise evaluation of endometrial cavity. Indications for endometrial biopsy include women ≥45 years of age, failed or ineffective treatment, persistent intermenstrual bleeding and co-existence of risk factors demonstrated in Figure 2.
3.3 Postmenopausal bleeding
Hysteroscopy is established as the gold standard in the evaluation of AUB in postmenopausal women, eliminating the false-negative results of blind biopsy by direct visualisation of the endometrial cavity and enabling targeted biopsy if warranted [14]. It allows full visualisation of the endocervix, endometrial cavity and tubal ostia, permitting diagnosis of endometrial lesions that may be missed with blind endometrial sampling, TVS or even saline infusion sonography (SIS). Moreover, vaginoscopic technique to perform office hysteroscopy can also be employed for careful examination of possible vaginal and cervical lesion that may be responsible for abnormal uterine bleeding. This approach also reduces discomfort in women, including virgins, older women and those with moderate stenosis of the cervical os who would have required general anaesthesia otherwise. The sensitivity, specificity and high precision of hysteroscopy are well established. With miniaturisation of hysteroscopes and newer treatment techniques such as bipolar devices and hysteroscopic tissue removal systems, outpatient hysteroscopy is no longer just a diagnostic test but can offer one stop treatment to women presenting with AUB [15, 16, 17].
4. Outpatient operative hysteroscocopy
4.1 Hysteroscopic polypectomy
Uterine polyps are focal endometrial outgrowths that may appear anywhere in the uterine cavity (Figure 4). They comprise of a variable amount of glands, stroma and blood vessels. Endometrial polyps are commonly found in combination with AUB. They affect women of reproductive age as well as postmenopausal women. Their underlying aetiology is unsure, but most are benign. Hysteroscopy is the gold standard diagnostic test. Diagnosis at outpatient hysteroscopy allows for simultaneous surgical removal, which is convenient for most women. Polyps should be removed in entirety in women with post-menopausal bleeding because 6% of the polyps harbour atypical endometrial hyperplasia or cancer particularly at the base [18, 19, 20, 21].
Outpatient polypectomy has been shown to be non-inferior to the inpatient procedure [22].
Uterine polypectomy could only be performed in the past using blind procedures, such as curettage and blind avulsion with forceps. To introduce such instruments required dilatation of the cervix and manipulation within the uterine cavity, that necessitated general anaesthesia. Developments in hysteroscopic equipment have enabled polyps to be removed using fine mechanical and electrosurgical tools, which are introduced down a 5- or 7-French rigid operating hysteroscope, and lately, the development of bespoke tissue removal systems. These techniques involve hysteroscopic assessment of uterine cavity, removal of the polyp from the uterine wall and retrieval using the same kit.
The enhanced fastidiousness of surgery and bypassing the requisite for routine significant cervical dilatation have empowered this to become a useful procedure, which can be performed in the office. Often local anaesthesia is not required, especially when using miniature hysteroscopes and employing vaginoscopic technique. Intracervical or paracervical injection of local anaesthesia may be used if cervical dilatation is required [23].
The results of the OPT trial exhibited that outpatient polypectomy was comparable to inpatient polypectomy for the effective mitigation of uterine bleeding due to uterine polyps. At 6 months, 73% of women in the outpatient treatment group and 80% in the inpatient treatment group were effectively cured, and the treatment effects were sustained at 12 and 24 months.
A patient preference study was conducted alongside this RCT which demonstrated a strong treatment setting preference. Nearly, 81% women in this study expressed an inclination for outpatient treatment, and a formal structured interview and thematic analysis established that the overall convenience and feasibility of the outpatient procedure, precluding hospital admission and time off work was highly valued by the women and outweighed the discomfort of the procedure [24].
4.2 Outpatient endometrial ablation
Heavy menstrual bleeding affects one in five premenopausal women and significantly impairs quality of life. There is evidence to offer endometrial ablation as a first line surgical option for the management of heavy menstrual bleeding. Hysteroscopy and endometrial biopsy should be performed prior to the procedure to rule out any organic pathology and after the procedure to rule out uterine perforation. Endometrial ablation in outpatient setting is associated with shorter hospital stay and quicker recovery. The development of newer (second generation) endometrial ablation techniques has empowered clinicians to set up a comprehensive outpatient service to treat heavy menstrual bleeding effectively without the need for general anaesthetic or conscious sedation. An observational study was performed in ladies with heavy menstrual bleeding who consented to have endometrial ablation in the outpatient setting under local anaesthetic. Once started, the ablation procedure did not have to be abandoned. Eighty-nine percent women went home immediately. Ninety percent expressed that they would have ambulatory hysteroscopic procedure if required in future. Endometrial ablation has conventionally been performed under general anaesthesia as a day case procedure. With new second-generation devices, which enable shorter treatment times, it has become more practical to perform the procedure in outpatient setting. Gynaecologists should continue to offer outpatient endometrial ablation to appropriately selected patients with abnormal uterine bleeding, with adequate counselling regarding possible pain and discomfort and alternative options [25].
Hysteroscopy under direct vision can be considered as the gold standard for examination of the uterine cavity, bypassing the significant limitations and possible complications of blind procedures. Modern technological advancements have brought ambulatory hysteroscopy to a mainstay in modern gynaecological practice.
The “see & treat hysteroscopy”, has revolutionised the management of abnormal uterine bleeding in all age groups. It has reduced the distinction between diagnostic and operative procedure, introducing the concept of a one step procedure perfectly amalgamating the treatment side with the diagnostic work-up. The use of miniaturised mechanical instruments together with the use of small diameter scopes with working channels and continuous flow systems, has enabled “see & treat” hysteroscopy in the office setting [26].
Outpatient hysteroscopy with direct visualisation represents the optimal diagnostic modality for abnormal uterine bleeding in premenopausal and postmenopausal women as well as treatment option for heavy menstrual bleeding, endometrial polyp, submucosal fibroid type 0 to 2, intrauterine adhesions and uterine septum. It provides cavity assessment in patients with subfertility as well [27]. Most women believe that the overall convenience of the office based procedure outweighs the pain and discomfort experienced and opt for the office procedure if required in future [28]. Hysteroscopy is generally a safe procedure and the uncommon complications such as infection, uterine perforation and fluid overload can be minimised by training, meticulous technique and modern equipment [29, 30].
Acknowledgments
Figures and videos “courtesy of HOLOGIC, Inc. and affiliates.”
Conflict of interest
The author declares no conflict of interest.
\n',keywords:"outpatient hysteroscopy, office hysteroscopy, ambulatory hysteroscopy, vaginoscopy, polypectomy",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/75943.pdf",chapterXML:"https://mts.intechopen.com/source/xml/75943.xml",downloadPdfUrl:"/chapter/pdf-download/75943",previewPdfUrl:"/chapter/pdf-preview/75943",totalDownloads:223,totalViews:0,totalCrossrefCites:0,totalDimensionsCites:0,totalAltmetricsMentions:0,impactScore:0,impactScorePercentile:43,impactScoreQuartile:2,hasAltmetrics:0,dateSubmitted:"February 20th 2021",dateReviewed:"March 8th 2021",datePrePublished:"March 25th 2021",datePublished:"February 9th 2022",dateFinished:"March 25th 2021",readingETA:"0",abstract:"Hysteroscopy is a gynaecological procedure that has developed into an important tool to identify endometrial abnormality. It offers direct examination of the uterine cavity and tubal ostia and offers the option of performing targeted biopsy of suspected lesions that can be missed by blind procedures. In a large number of cases, the intrauterine lesions can be diagnosed and treated at the same setting as one step approach (“see and treat”). For example, endometrial polyps can be identified and removed; intrauterine adhesions may be divided in the office owing to the practicability of operative saline hysteroscopy, vaginoscopic approach and the convenience of miniature hysteroscopes. There is decent evidence that hysteroscopy in the outpatient clinic setting is preferred by the patients, associated with low risk of complications, quicker recovery time and reduced cost. Technological advances have led to development of high definition miniature hysteroscopes without negotiating optical performance, and hence making hysteroscopy an ingenuous, safe and trusted office procedure. Recent advances such as bipolar electrosurgery, endometrial ablation devices, morcellators and tissue retrieval system has transformed the surgical technique. This modernization of hysteroscopy completely revolutionised the approach to the management of intrauterine pathologies, moving from a blind procedure under general anaesthesia to directly visualised procedure under no or local anaesthesia, offering diagnostic as well as therapeutic procedures that should be at the disposal of every modern gynaecologist.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/75943",risUrl:"/chapter/ris/75943",book:{id:"9811",slug:"ultimate-guide-to-outpatient-care"},signatures:"Ayesha Ajmi",authors:[{id:"331486",title:"Dr.",name:"Ayesha",middleName:null,surname:"Ajmi",fullName:"Ayesha Ajmi",slug:"ayesha-ajmi",email:"ayeshaqasim77@hotmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Vaginoscopy",level:"1"},{id:"sec_3",title:"3. Outpatient diagnostic hysteroscopy",level:"1"},{id:"sec_3_2",title:"3.1 Abnormal uterine bleeding (AUB) in women of reproductive age group",level:"2"},{id:"sec_4_2",title:"3.2 Perimenopausal bleeding",level:"2"},{id:"sec_5_2",title:"3.3 Postmenopausal bleeding",level:"2"},{id:"sec_7",title:"4. Outpatient operative hysteroscocopy",level:"1"},{id:"sec_7_2",title:"4.1 Hysteroscopic polypectomy",level:"2"},{id:"sec_8_2",title:"4.2 Outpatient endometrial ablation",level:"2"},{id:"sec_10",title:"5. Conclusions",level:"1"},{id:"sec_11",title:"Acknowledgments",level:"1"},{id:"sec_14",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Heavy menstrual bleeding: assessment and management| Guidance and guidelines | NICE [Internet] [www.nice.org.uk/guidance/ng88]. Accessed 09 March 2019 Google Scholar'},{id:"B2",body:'Clark T.J., Gupta J.K.: Handbook of outpatient hysteroscopy: a complete guide to diagnosis and therapy.2005.CRC PressBoca Raton, FL'},{id:"B3",body:'Kayatas S, Meseci E, Tosun OA, Arinkan SA, Uygur L, Api M. Experience of hysteroscopy indications and complications in 5,474 cases. Clin Exp Obstet Gynecol. 2014;41(4):451-454'},{id:"B4",body:'Bettocchi S, Ceci O, Vicino M, Marello F, Impedovo L, Selvaggi L. Diagnostic inadequacy of dilatation and curettage. Fertil Steril. 2001;75(4):803-805'},{id:"B5",body:'Cicinelli E. Hysteroscopy without anesthesia: review of recent literature. J Minim Invasive Gynecol.2010;17(6):703-708'},{id:"B6",body:'O’Flynn H, Murphy LL, Ahmad G, Watson AJ. Pain relief in outpatient hysteroscopy: a survey of current UK clinical practice. Eur J Obstet Gynecol Reprod Biol. 2011;154(1):9-15'},{id:"B7",body:'Smith, PP, Kolhe, S, O\'Connor, S, Clark, TJ. Vaginoscopy Against Standard Treatment: a randomised controlled trial. BJOG 2019; 126: 891-899'},{id:"B8",body:'Bettocchi S, Selvaggi L. A vaginoscopic approach to reduce the pain of office hysteroscopy. J Am Assoc Gynecol Laparosc. 1997;4(2):255-258'},{id:"B9",body:'Bakour SH, Jones SE, O’Donovan P. Ambulatory hysteroscopy: evidence-based guide to diagnosis and therapy. Best Pract Res Clin Obstet Gynaecol. 2006;20(6):953-975'},{id:"B10",body:'Bradley LD. Diagnosis of abnormal uterine bleeding with biopsy or hysteroscopy. Menopause. 2011;18(4):425-433'},{id:"B11",body:'Kolhe S. Management of abnormal uterine bleeding - focus on ambulatory hysteroscopy. Int J Womens Health. 2018 Mar 22;10:127-136. doi: 10.2147/IJWH.S98579. PMID: 29606892; PMCID: PMC5868607'},{id:"B12",body:'Van Dongen H, de Kroon CD, Jacobi CE, Trimbos JB, Jansen FW. Diagnostic hysteroscopy in abnormal uterine bleeding: a systematic review and meta-analysis. BJOG. 2007;114(6):664-675'},{id:"B13",body:'Munro MG, Critchley HO, Broder MS, Fraser IS, FIGO Working Group on Menstrual Disorders FIGO classification system (PALM-COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age. Int J Gynaecol Obstet. 2011;113(1):3-13. [PubMed] [Google Scholar]'},{id:"B14",body:'Cooper NA, Barton PM, Breijer M, et al. Cost-effectiveness of diagnostic strategies for the management of abnormal uterine bleeding (heavy menstrual bleeding and post-menopausal bleeding): a decision analysis. Health Technol Assess. 2014;18(24):1-201. v–vi'},{id:"B15",body:'Angioni S, Loddo A, Milano F, Piras B, Minerba L, Melis GB. Detection of benign intracavitary lesions in postmenopausal women with abnormal uterine bleeding: a prospective comparative study on outpatient hysteroscopy and blind biopsy. J Minim Invasive Gynecol. 2008;15(1):87-91. [PubMed] [Google Scholar]'},{id:"B16",body:'Grimbizis GF, Tsolakidis D, Mikos T, et al. A prospective comparison of transvaginal ultrasound, saline infusion sonohysterography, and diagnostic hysteroscopy in the evaluation of endometrial pathology. Fertil Steril. 2010;94(7):2720-2725. [PubMed] [Google Scholar'},{id:"B17",body:'T. Justin Clark, Helen Stevenson,Endometrial Polyps and Abnormal Uterine Bleeding (AUB-P): What is the relationship, how are they diagnosed and how are they treated?,Best Practice & Research Clinical Obstetrics & Gynaecology,2017;40:89-104 ISSN 1521-6934, https://doi.org/10.1016/j.bpobgyn.2016.09.005'},{id:"B18",body:'Elfayomy A.K., Habib F.A., Alkabalawy M.A.: Role of hysteroscopy in the detection of endometrial pathologies in women presenting with postmenopausal bleeding and thickened endometrium. Arch Gynecol Obstet 2012; 285: pp. 839-843'},{id:"B19",body:'Nathani F, Clark TJ. Uterine polypectomy in the management of abnormal uterine bleeding: a systematic review. J Minim Invasive Gynecol. 2006;13(4):260-268'},{id:"B20",body:'Bakour S.H., Khan K.S., Gupta J.K.: The risk of premalignant and malignant pathology in endometrial polyps. Acta Obstet Gynecol Scand 2002; 8: pp. 182-183'},{id:"B21",body:'Daniele A, Ferrero A, Maggiorotto F, Perrini G, Volpi E, Sismondi P. Suspecting malignancy in endometrial polyps: value of hysteroscopy. Tumori. 2013;99(2):204-209'},{id:"B22",body:'Cooper NA, Clark TJ, Middleton L, et al. Outpatient versus inpatient uterine polyp treatment for abnormal uterine bleeding: randomised controlled non-inferiority study. BMJ. 2015;350:h1398'},{id:"B23",body:'Garuti G., Centinaio G., Luerti M.: Outpatient hysteroscopic polypectomy in postmenopausal women: a comparison between mechanical and electrosurgical resection. J Minim Invasive Gynecol 2008; 15: pp. 595-600'},{id:"B24",body:'Clark T.J., Middleton L.J., Cooper N.A.M., et. al.: A randomised controlled trial of outpatient versus inpatient Polyp Treatment (OPT) for abnormal uterine bleeding. Health Technol Assess 2015; 19:'},{id:"B25",body:'Ayesha Ajmi & Sangeeta Das (2020): Outpatient endometrial ablation: audit of outcomes and patient satisfaction, Journal of Obstetrics and Gynaecology, DOI: 10.1080/01443615.2019.1700945'},{id:"B26",body:'Campo R, Santangelo F, Gordts S, et al. Outpatient hysteroscopy. Facts Views Vis Obgyn. 2018;10(3):115-122'},{id:"B27",body:'Salazar CA, Isaacson KB. Office Operative Hysteroscopy: An Update. J Minim Invasive Gynecol. 2018 Feb;25(2):199-208. doi: 10.1016/j.jmig.2017.08.009. Epub 2017 Aug 10. PMID: 28803811'},{id:"B28",body:'De Iaco P, Marabini A, Stefanetti M, Del Vecchio C, Bovicelli L. Acceptability and pain of outpatient hysteroscopy. J Am Assoc Gynecol Laparosc. 2000;7(1):71-75'},{id:"B29",body:'Stankova T, Ganovska A, Stoianova M, Kovachev S. Complications of diagnostic and operative hysteroscopy – review. Akush Ginekol. 2015;54(8):21-27'},{id:"B30",body:'McGurgan PM, McIlwaine P. Complications of hysteroscopy and how to avoid them. Best Pract Res Clin Obstet Gynaecol. 2015;29(7):982-993'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Ayesha Ajmi",address:"ayesha.q.ajmi@gmail.com",affiliation:'
Bolton Foundation NHS Trust, Bolton, UK
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1. Introduction
Psoriasis is a chronic immune cell-mediated inflammatory skin disease characterized by the formation of scaly indurated erythema occurring most commonly on the elbows, knees, scalp, and lower back, but any skin surface can be involved [1]. The highly visible condition greatly affects people’s quality of life that can be stigmatizing. People with psoriasis are at an increased risk of developing other chronic and serious health conditions. Comorbidities include psoriatic arthritis, inflammatory bowel disease, hypertension, diabetes, obesity, and depression. The worldwide prevalence of psoriasis is estimated to be 2–4%, rising up to 9.7% in Scandinavian countries [2, 3].
Psoriasis can be classified into mild, moderate, or severe disease according to the Psoriasis Area and Severity Index (PASI). Treatment choices are often based on the severity of disease: mild disease often managed with topical therapy, and moderate-to-severe disease requiring systemic therapy for control, often with concomitant topical therapy [4, 5, 6]. Effects of systemic therapy in synergy with topical agents may help reduce the burden and achieve better quality of life that psoriasis patients deserve. In mild-to-moderate, as well as moderate-to-severe, psoriasis, 70–80% of patients start with topical agents and continue to use them with other active therapies.
Currently, high-potency topical glucocorticoid and vitamin D derivatives are the main treatments for psoriasis [7, 8, 9]. Topical glucocorticoids are effective but their use is limited to no more than 2–8 weeks due to their long-term side effects, such as atrophy [10]. This is particularly true in more sensitive areas, such as the face or intertriginous areas. There are numerous reports of low satisfaction for these topical agents [11]. Hence, there remains great unmet medical needs for developing a highly efficacious and safe topical treatment in psoriasis.
2. IL-23/IL-17 axis is a major immune pathway in the development of psoriasis
2.1 Psoriasis is a TH17-driven disease
In psoriatic skin, immune response is overactive. Excess amounts of cytokines were produced, which caused prolonged inflammation and abnormal proliferation of keratinocytes. In recent decades, genetic and immunological studies have made progress in dissecting the mechanisms of psoriasis. Psoriasis was previously thought to be an interferon (IFN)-γ-producing T helper (TH) 1-driven autoimmune inflammatory disease [12, 13]. However, the discovery of TH17 cells shifted the view of psoriasis as an TH17-dependent pathology rather than TH1 cells [12, 13, 14].
IFN-γ is increased in serum from psoriasis patients and its mRNA is elevated in skin lesions [15, 16]. It was hypothesized that IFNγ blockade could decrease disease activity due to the appreciation of elevated IFN-γ expression in psoriasis. A neutralized humanized anti-IFN-γ antibody, HuZAF, was developed and tested in two small pilot studies between 2001 and 2003 [17]. In the study that was designed to determine the efficacy of miltidose HuZAF, of all 10 patients treated four times with 10 mg/kg of HuZAF, only 1 patient (10%) achieved a significant clinical response. The expression of CXCL9 was significantly suppressed by HuZAF through week 12. This finding suggests IFN-γ was successfully blocked by HuZAF in these patients since CXCL9 is heavily regulated by IFN-γ. The limited clinical efficacy of IFNγ blockade by HuZAF in patients with psoriasis suggest that infiltration of TH1 cells in psoriatic plaque likely contribute little to the pathogenesis of this disease.
The naive T cells are differentiated into TH1, TH2, TH17, or Treg cells depending on specific cytokines released by antigen-presenting cells and T-cell receptor stimulation and costimulation. The differentiation of TH17 cells are induced by interleukin (IL)-6, transforming growth factor (TGF)-β, and IL-21 [18, 19, 20]. Maintenance of TH17 population requires IL-23, a heterodimeric cytokine expressed by macrophages and dendritic cells [21, 22]. The intracellular transcription factors RORγt and STAT3 are also critical in the development of TH17 cells. Binding of IL-23 to IL-23 receptor (IL23R) attracts a heterodimer of kinase JAK2 and TYK2 and induces phosphorylation of STAT3, which enhances RORγ-mediated transcription of IL-17A and IL-17F [23, 24]. TGF-β1 is abundantly expressed in plasma and scales from psoriatic lesions and transgenic mice that overproduce human TGF-β1 in basal keratinocytes exhibit classic signs of psoriasis [25]. Similar observations were made with STAT3, which is overproduced in psoriasis, and its transgenic mice also exhibit psoriasis-like phenotypes [26]. Under the regulation of IL-23, activated TH17 cells in the skin produce high levels of IL-17, which is often referred to as the IL-23/IL-17 axis.
2.2 IL-23 stimulates TH17 cell survival and proliferation
On developing TH17 cells, the expression of IL-23R is induced by intracellular signaling through RORγt and STAT3 and extracellular TGF-β1. The expression of IL-23R then promotes responsiveness to IL-23, which is the key cytokine in the survival and proliferation of TH17 cells [27, 28]. In psoriasis lesions, IL-23 is overproduced by dendritic cells and keratinocytes [29, 30, 31].
The importance of IL-23 in psoriasis has been confirmed by genetic studies. Polymorphisms in both subunits of IL-23, IL23A (p19) and IL12B (p40), and IL23R have been reported to be associated with an increased risk of psoriasis in North Americans, Europeans and Asians [32, 33]. A common risk haplotype of IL-23R, proline at amino acid 310 and arginine at amino acid 381, was identified. A single amino acid change from arginine to glutamine at amino acid 381 in IL-23R was found to be protective against psoriasis. Interestingly, this amino acid is located at the JAK2 kinase-binding domain of IL-23R. It is likely the change to glutamine breaks the IL-23R signaling and blocks inflammatory response induced by TH17 cell. In mouse studies, intradermal injection of recombinant IL-23 in normal-appearing skin induces skin inflammation and produces erythematous, thick and scaly skin with histologic features reminiscent of psoriasis [34], and IL-23 deficient mice were resistant to imiquimod-induced psoriasis-like inflammation [35]. Similarly, mice lacking IL-23 are resistant to experimental autoimmune encephalomyelitis (EAE) [21].
IL-23 belongs to the IL-12 family of cytokines and consists of two subunits: p19 and p40. P19 is unique for IL-23 and p40 is shared with IL-12. There are several lines of evidence to demonstrate the central role of IL-23, but not IL-12, in the pathogenesis of psoriasis [14]. The high expression of p19 and p40, but not IL-12 specific p35 expression, was observed in psoriatic lesions as compared to nonlesional skin [36]. Mice lacking the p35 subunit of IL-12 (Il12a−/−) or the IL-12-respectific receptor subunit (Il12rb2−/−) significantly increased skin inflammation, consistent with the observation in the EAE model of multiple sclerosis that IL-12 knockout mice led to worsening inflammation [37, 21]. In transgenic mice, overexpression of individual subunits of IL-23 leads to inflammation [38, 39]. Ubiquitous transgenic expression of the IL-23 subunit p19 induced a striking phenotype characterized by multiorgan inflammation, runting, infertility and death before 3 month of age [38]. Furthermore, p40 transgenic mice constitutively produce IL-23 (p19/p40), but not IL-12 (p35/p40), in basal keratinocytes by secretion of transgenic p40 with endogenous p19 [39]. p40 transgenic mice cause an inflammatory skin disease, similar to that of intradermal injection of recombinant IL-23 in mice, confirming the provital role of IL-23, but not IL-12, in psoriasis pathogenesis.
2.3 IL-17 is a central proinflammatory effector cytokine in psoriasis
IL-23 is required for autoimmune inflammation mediated by TH17 cells and produces large amounts of IL-17 in vivo [40]. IL-23 injection into skin of wild-type mice induces psoriasis-like symptoms, but not in IL-17 knockout mice, and if the wild-type mice are pre-treated with IL-17 antibody, IL-23-induced disease is blocked, suggesting that IL-17 is downstream of IL-23 and critical role in psoriasis pathogenesis [12].
Among six isoforms of IL-17, IL-17A and IL-17F are the most pathogenic in psoriasis [31]. IL-17A is often referred to as IL-17, for which the TH17 cell lineage is named. Besides TH17 cells, a large number of other skin cells also produce IL-17, including γδ T cells, αβ T cells, neutrophils, mast cells, ILC3s and Tc17 cells. Some production is independent of IL-23 [12]. In psoriatic skin, IL-17 expression is higher, and the number of TH17 cells, γδ T cells, Tc17 cells were all greatly increased compared to normal skin [30, 41]. Genes that are up-regulated in keratinocytes treated by IL-17A in vitro, are corresponded to the genes up-regulated in psoriasis lesions, and the overlap is bigger than that by TNF-α or IFN-γ [42]. In response to IL-17, keratinocytes produce a variety of antimicrobial peptides (AMPs) and chemokines. They induce flammation and neutrophil recruitment and lead to hyperproliferation of the epidermis and aberrant differentiation of keratinocytes [43].
Even in nonlesional skin from psoriasis patients, expression of IL-17-downstream genes is higher compared to normal skin, and disease severity is significantly correlated with levels of IL-17 and TNF-α in blood. There is also a strong correlation between PASI scores and pathways related to IL-17 [44]. All the evidence suggests that IL-17 is the central effector cytokine in psoriasis.
3. Clinical proof of concept of targeting the IL-23/IL-17 axis for the treatment of plaque psoriasis
Table 1 summarizes biologics approved by the US Food and Drug Administration (FDA) for the systemic treatment of plaque psoriasis [45, 46, 47, 48]. These biologics specifically target cytokines and the receptors involved in psoriasis pathogenesis. Treatment with biologics results in a greater efficacy and better safety profile compared to conventional systemic agents that do not target specific components of the immune system, and demonstrates the essential role of the IL-23/IL-17 axis in psoriasis [49, 50].
Drug Class
Target molecule
Therapeutic Agent (Trade name)
Year of FDA approval
Dose and Administration
Other Indications
TNF blocker (biologics)
TNF
Etanercept (Enbrel®)
2004
50 mg twice weekly for 3 months, followed by 50 mg once weekly; S.C. injection
RA; JIA; PsA; AS
Infliximab (Remicade®)
2006
5 mg/kg at weeks 0, 2, 6 followed by 5 mg/kg every 8 weeks; I.V. infusion
RA; PsA; AS; CD; UC
Adalimumab (Humira®)
2008
80 mg on day 1 followed by 40 mg every other week; S.C. injection
RA; JIA; PsA; AS; CD; UC; HS; Uveitis
Certolizumab pegol (Cimzia®)
2018
400 mg every other week; S.C. injection
RA; PsA; AS; CD; non-radio -graphic AS
IL-12/23 antagonist (biologics)
IL-12/23 p40
Ustekinumab (Stelara®)
2009
45 mg or 90 mg at weeks 0, 4, followed by 45 mg or 90 mg every 12 weeks; S.C. injection
PsA; CD; UC
IL-17 antagonist (biologics)
IL-17A
Secukinumab (Cosentyx®)
2015
300 mg at weeks 0, 1, 2, 3, 4, followed by 300 mg every 4 weeks; S.C. injection
PsA; AS; non-radio -graphic AS
Ixekizumab (Taltz®)
2016
160 mg at week 0; 80 mg every 2 weeks for 3 months, followed by 80 mg every 4 weeks; S.C. injection
PsA; AS; non-radiographic AS
IL-17RA
Brodalumab (Siliq®-US; Kyntheum®-Europe)
2017
210 mg at weeks 0, 1, 2, followed by 210 mg every 2 weeks; S.C. injection
none
IL-23 antagonist (biologics)
IL-23 p19
Guselkumab (Tremfya®)
2017
100 mg at weeks 0, 4, followed by 100 mg every 8 weeks; S.C. injection
PsA
Tildrakizumab (Ilumya™)
2018
100 mg at weeks 0, 4, followed by 100 mg every 12 weeks; S.C. injection
none
Risankizumab (Skyrizi™)
2019
150 mg at weeks 0, 4, followed by 150 mg every 12 weeks; S.C. injection
none
Table 1.
FDA approved biologics for systemic treatment of moderate-to-severe plaque psoriasis.
The first-generation anti-psoriatic biologics targeting cytokines focussed on TNF, an inflammatory cytokine implicated in psoriasis pathogenesis for a long time. High levels of TNF and its receptors (TNFR1 and TNFR2) are expressed in psoriatic lesional skin [51]. Four TNF blockers were approved by the FDA for psoriasis treatment (Table 1). TNF inhibition showed good therapeutic efficacy. At week 24, about 50 to 80 percent of patients reached 75% improvement in the psoriasis area and severity index (PASI75), and 10 to 20 percent got PASI100, which means 100% improvement [14]. Infliximab is the most efficacious TNF blocker followed by adalimumab and etanercept [50]. The primary mechanism of action of TNF blockers in improvement of psoriasis treatment is most likely due to its indirect effect on IL-23/IL-17 signaling pathway. The therapeutic effects of TNF blockade are observed to be associated with a strong reduction of IL-17-dependent genes [52]. In addition, TNF induces IL-23 expression in keratinocytes [53]. The exact roles of TNF in the pathogenesis of psoriasis are not yet completely understood.
Nevertheless, TNF is a versatile cytokine that not only involves inflammatory immune responses, but also contributes to cell death, cell cycling and tissue remodeling [54]. TNF blockers are well-known associated risk factors of serious infections, such as lower respiratory tract and skin and soft tissue infections like pneumonia and cellulitis [55]. After initial treatment of around 2 weeks, 2% ~ 5% of the patients developed paradoxical psoriasis: new lesions developed or the existing lesions got worse [54]. This side effect also happened when TNF blockers were used to treat other autoimmune diseases, including Crohn’s disease and rheumatoid arthritis [53, 56]. It has been reported that IL-17A expression was strong in skin lesions from patients who had paradoxical psoriasis and needed other therapy [57]. This suggests that under some conditions, IL-17 is not down-regulated while blocking TNFα so that skin lesions continue to develop.
After TNF blockers, biologics that directly target the IL-23/IL-17 axis have been developed. The second-generation monoclonal antibody, ustekinumab, is targeting the subunit p40 common to IL-12 and IL-23, blocking signaling of their cognate receptors that induce a nonspecific inhibition of TH1 and TH17 [58, 59]. Ustekinumab has efficacy similar to TNFα inhibitors. It is better than etanercept, but not as good as infliximab. Ustekinumab received FDA approval for the treatment of moderate-to-severe psoriasis in 2009 (Table 1).
IL-17 is a central proinflammatory effector cytokine downstream of IL-23 and implicated in the pathogenesis of psoriasis. The third-generation monoclonal antibodies that neutralize IL-17 became available for the treatment of psoriasis (Table 1). Secukinumab and ixekizumab are human monoclonal antibodies against IL-17A. Brodalumab is blocking IL-17RA, which is the receptor for IL-17A, IL-17C, IL-17E, IL-17F and IL-17 A/F heterodimers. As IL-17A, IL-17C and IL-17F are all up-regulated in psoriatic skin [31], it is likely that brodalumab would have a better effect. In a study that brodalumab was given to patients who experienced unsuccessful treatment with either secukinumab or ixekizumab, PASI75, PASI90 and PASI100 scores were achieved in 69%, 44% and 28% of patients [60]. In phase III trials, 30–60% of patients treated with IL-17 antagonists reached PASI100 [61, 62, 63, 64, 65]. The superior efficacy of IL-17 blockade over neutralizing IL-12/IL23 and blocking TNF has been demonstrated in head-to-head clinical trials of brodalumab versus ustekinumab [62] and ixekizumab versus etanercept [61, 62].
The most common adverse effects of IL-17 antagonists are nasopharyngitis, upper respiratory tract infections, mucocutaneous candidiasis, transient neutropenia and injection site reactions. Mucocutaneous candidiasis observed by IL-17 inhibition or inborn genetic errors of IL-17 gene [66] suggests the innate, protective role of IL-17 against microbial pathogens on the skin. There is a black box warning for brodalumab due to the results from AMAGINE 1 and 2, where four patients committed suicide during the treatment period [64, 65].
IL-23 is known as the master regulator of TH17 cells. A fourth-generation of monoclonal antibodies against p19 subunits of IL-23, guselkumab, tildrakizumab and risankizumab, have been approved for treatment of moderate-to-severe psoriasis (Table 1). In contrast to ustekinumab, these biologics target IL-23 by neutralizing the p19 subunit without disrupting the IL-12 signaling pathway. Selectively targeting IL-23p19 provides better efficacy than ustekinumab [50]. IL-23 antagonists can reach a PASI90 in more than 50% of patients, confirming the provital role of IL-23 in the pathogenesis of psoriasis [67, 68, 69].
The head-to-head trial of guselkumab versus ustekinumab demonstrates superiority of selectively targeting p19 subunit of IL-23 among patients who had an inadequate response to ustekinumab with similar types of safety profiles [70]. As demonstrated by clinical trial outcomes, double blockade of IL-12 and IL-23 with ustekinumab resulted in lesser disease improvement versus single blockade of IL-23, confirming IL-23, but not IL-12, is a major player in psoriasis.
In addition, IL-23p19 antagonists exhibit significantly higher efficacy compared to all tested TNF blockers while maintaining a favorable safety profile [71, 69]. For example, guselkumab was superior (p < 0.001) to adalimumab for PASI90 response at week 48 (76.3% versus 47.9%), respectively. Compared with IL-17 antagonists, guselkumab exhibits a longer duration of therapeutic effect in patients with psoriasis [69]. This is probably because IL-23 is a key driver of TH17 cell differentiation and survival, and an upstream regulator of IL-17A. IL-17 producing cells are dependent on IL-23 for survival. IL-23 stimulates production of not only IL-17, but also other TH17 cytokines (for example, IL-22) by other immune cell types, including γδ T cells.
The most common adverse events with the use of guselkumab and tildrakizumab are nasopharyngitis, upper respiratory tract infections, and headaches [67, 68, 69]. In contrast to IL-17 antagonists, the rate of mucocutaneous candidiasis was infrequent and comparable to healthy control subjects.
In conclusion, clinical outcomes of these biologics targeting IL-23p19 and IL17 are a strong argument for the IL-23/IL-17 axis in driving disease pathology. These molecular targeted therapies not only remarkably alleviate symptoms but also provide a deep understanding of the molecular mechanism of psoriatic disease.
4. New targeted therapeutics in development for topical treatment of psoriasis
Targeting a spectrum of inflammatory mediators involved in the pathogenesis of psoriasis will ensure a favorable safety profile and limited side effects. As discussed above, biological treatment, along with evolving systemic therapy, has revolutionized severe psoriasis management. Development of new and effective biologics has made much progress in our understanding of psoriasis immunopathology. Topical therapy implies good compliance for the psoriatic patients, few adverse systemic reactions as compared to systemic medications. However, biologics targeting proinflammatory cytokines are not suitable for topical route delivery due to the large size and poor permeability into skin. Small molecules targeting intracellular signaling pathway have some advantages over biologic agents, particularly the possibility of topical administration, lack of immunogenicity, the simplified synthesis processes, low-cost production, placing these drugs in a very attractive position for future drug discovery and development in topical treatment of psoriasis. New topical targeted therapeutics undergoing efficacy and safety studies are summarized in Table 2 based on the information available from the website of ClinicalTrials.gov [72].
RORγt is a master transcription factor of TH17 cells, which activates the transcription of IL-23 receptor gene as well as pro-inflammatory cytokines such as IL-17A, IL-17F, IL-21, and IL-22, and enhances the inflammatory process. Clinical success of biologics in the IL23/IL17 axis suggests that inhibiting RORγ could be an effective alternative therapy for psoriasis.
Vitae Pharmaceuticals (acquired by Allergan, later by Abbvie) developed an orally active RORγt antagonist VTP-43742 for the treatment of autoimmune diseases, including psoriasis through suppression of IL-17A production and down-regulation of the IL-23 receptor [73]. VTP-43742 with high systemic exposure demonstrated a clear signal of efficacy over a short four-week period from a Phase 2a clinical trial in psoriatic patients [74]. It provides a proof of concept of RORγ antagonists for the treatment of psoriasis, consistent with the clinical success of biologics in the IL23/IL17 axis.
Nevertheless, two drug candidates terminated their clinical trials due to potential safety liability. Four patients in the 700 mg VTP-43742 dose group showed reversible transaminase elevations, which led the company to terminate the development of VTP-43742. In addition, Takeda Pharmaceutical Company terminated a phase 1 trial of oral RORγ antagonist TAK828 for evaluation of the safety, tolerability, pharmacokinetics, and pharmacodynamics of escalating multiple doses in healthy volunteers in the United states (NCT02817516). The decision was based on critical non-monitorable toxicology findings in both monkeys and rats, combined with the potential for teratogenicity in humans [75].
RORγ has two isoforms, RORγ1 and RORγ2 (most commonly referred to as RORγt) [76]. RORγt is a differentially spliced isoform of RORγ1, 19 amino acids shorter at N-terminus. The biochemical assay for evaluation of the compounds using LBD of the receptor will result in pan-RORγ antagonists. RORγt is exclusively expressed in a few distinct cell types of the immune system, including Th17, Tc17, γδ T cells and regulatory T cells [43, 77, 78, 79, 80] whereas, RORγ1 exhibits oscillatory expression in liver, brown adipose tissue, and kidney [81, 76]. Systemic exposure of the Pan-RORγ antagonists may have off-target effects against the not-intended target, RORγ1, during the treatment of the diseases. In addition, a mouse genetics study indicated that 50% of embryonic RORγ deficient mice developed T-cell lymphoma [82]. Lymphoma was also observed in adult RORγ knockout mice with immune systems intact [83]. The phenotypes of RORγ knockout mice cause concerns of the consequences of systemic treatment of RORγ antagonists in the patients with psoriasis.
Developing RORγ antagonists with the skin-restricted exposure may alleviate the safety risk of systemic exposure while still maintaining similar efficacy as biologics in the IL-23/IL17 pathway, and may provide a new option as topical targeted therapeutics for psoriasis patients. Phase 1 trial of topical RORγ antagonist GSK2981278 for the treatment of psoriasis was not advanced further (Table 2) [84]. 0.03%, 0.1%, 0.8% and 4% GSK2981278 ointments were used in the tria, respectively. Across all doses, infiltrate thickness was not altered. Biomarker results did not support that the target was engaged. Although GSK2981278 was shown in vitro as a highly potent and selective antagonist of RORγ, the limited in vivo efficacy in reduction of epithermal thickness (23% reduction vs. placebo with imiquimod (IMQ) control at 1% GSK2981278 ointment) was observed in IMQ-induced mouse psoriasis-like inflammation model [85]. The skin exposure of GSK2981278 was not disclosed while its systemic exposure in mouse serum was relatively low [85]. It is speculated that insufficient drug exposure at the target site might be one of the reasons for its lacking efficacy in phase 1 trial [84].
More effort was then focused on developing RORγ antagonists in restricted exposure and prolonged action at the skin while being rapidly eliminated from the systemic circulation for topical therapy in psoriasis. ESR114 topical gel is a selective, potent inhibitor of RORγ designed to have its pharmacological activity targeted to the skin with minimal systemic absorption [86]. In 2019, Escalier Biosciences completed a phase I/II trial evaluating ESR-114 topical gel in patients with mild-to-moderate psoriasis in USA and Canada (NCT03630939, Table 2). Nevertheless, no trial results were disclosed yet. In addition, it was reported that a novel series of benzimidazole with RORγ antagonistic activity, SHR168442, was developed with desirable skin-restricted PK properties for a topical drug [87]. SHR168442 suppressed the IL-17 gene transcription, and reduced IL-17 cytokine secretion, and, more importantly, achieved skin-restricted exposure suitable for topical delivery. In the IMQ-induced and IL-23-induced psoriasis-like skin inflammation mouse models, SHR168442 ointment exhibited excellent efficacy, which correlated with the reduction of Th17 pathway cytokines, IL-17A, IL-6 and TNFα. This novel RORγ antagonist may represent a new option as topical targeted therapeutics for mild to moderate psoriasis patients. Results from further clinical evaluation of this specific mechanism for the treatment of mild to moderate psoriasis are highly anticipated.
4.2 JAK inhibitors
The Janus kinase–signal transducer and activator of transcription (JAK–STAT) pathway plays a crucial role in intracellular signaling of cytokine of many cellular processes, important in both normal and pathological states of immune-mediated inflammatory diseases [88]. There are four different types of JAK proteins: JAK1, JAK2, JAK3 and TYK2. The IL-23 receptor relies on a heterodimer of JAK2 and TYK2 for signal transduction, thus highlighting the role of JAKs in the pathogenesis of psoriasis and the therapeutic potential of JAK inhibitors in psoriasis. TYK2-deficient mice, as compared to wild-type mice, exhibit significantly reduced ear swelling and less epidermal hyperplasia when injected with IL-23 [89, 90]. In the absence of TYK2, the production of IL-17 and IL-22 and skin infiltration of various immune cells were also impaired. Taken together with the clinical success of biologics blocking either IL-23 or IL-17 signaling (Table 1), these results suggest the great potential for JAK inhibitors and, especially, for TYK2 inhibitors in the treatment of psoriasis.
JAK inhibitors are already on the market for rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis [24]. JAK inhibitors have been tested as potential treatments for psoriasis. The first generation of JAK inhibitors target multiple members of the JAK family and thus display a broader effect but also present more side effects. Many JAK inhibitors tested for oral treatment of psoriasis have only been examined in phase II trials except tofacitinib (reached phase III). It is doubtful that they will be tested further. In recent years, selective TYK2 inhibitors have been developed, and several phase III trials are in progress. The highly selective TYK2 inhibitor BMS-986165 has shown high efficacy toward psoriasis, confirming the important role of the IL-23/IL-17 axis in pathogenesis of psoriasis [91]. Several JAK inhibitors with different selectivity spectrums are under clinical development for the topical treatment of psoriasis (Table 2).
Tofacitinib (pan-JAK inhibitor) has been approved for the treatment of psoriatic arthritis, but not of psoriasis. Oral tofacitinib has been tested in phase III for psoriasis. Although tofacitinib shows a favorable clinical effect on plaque psoriasis symptoms, herpes zoster occurs during tofacitinib treatment, especially in Asian populations including the Japanese [48]. In phase 2b trial, the ointment formulation of tofacitinib was found to have no considerable effect at week 12 in comparison to that of the vehicle [92].
Ruxolitinib is a selective JAK1 and JAK2 inhibitor that inhibits various cytokines involved in the signaling of TH1 and TH17 pathways, including IL-12, IL-23 and IFNγ, which are associated with psoriasis. Its cream formulation has been approved by FDA for the treatment of atopic dermatitis, but not of psoriasis [93]. In phase II studies, ruxolitinib was studied as a topical ointment for mild-to-moderate psoriasis (Table 2). In an open phase 2 study conducted with 28 patients, a greater reduction in lesion severity score was observed for topical ruxolitinib as compared with vehicle and with calcipotriene [94]. The systemic absorption of the product was minimal. In a subsequent phase IIb, double-blind, randomed, vehicle-controlled study, 200 patients with mild-to-moderate chronic plaque psoriasis were treated with topical ruxolitinib for 3 months and the results indicated the mean PASI improvement was 40% compared with placebo [95]. Both studies reported the main adverse event was local irritation, which was more frequent in patients treated with placebo. To date, no phase III study of ruxolitinib in psoriasis has begun yet.
PF-06700841 is a potent dual inhibitor of TYK2 and JAK1, which was shown to be safe and well tolerated in the oral treatment at doses up to 200 mg once daily in a phase I clinical trial [96]. No other clinical trials with oral PF-06700841 in psoriasis are now ongoing. A phase IIb study of topical application of PF-06700841 cream involving patients with mild-to-moderate psoriasis (NCT03850483) was recently completed (April 20, 2021). The trial results are not yet available.
4.3 DNMT inhibitors
DUR-928 is an endogenous sulfated oxysterol that acts as an epigenetic regulator [97]. It binds to and inhibits the activity of DNMTs, DNMT-1, 3a and 3b, inhibiting DNA methylation, and thereby modulating the expression of the genes associated with stress response, lipid biosynthesis and cell death. Improvement of cell survival and reduction of lipotoxicity and inflammation by DUR-928 were observed in animal models and from DURECT’s clinical trials in alcohol-associated hepatitis (AH) and nonalcoholic steatohepatitis (NASH). The rationale of topical application of DUR-928 in psoriasis is not clear. A phase IIb study of topical application of DUR-928 topical solution in patients with mild-to-moderate psoriasis (NCT03837743) was completed on August 20, 2020 (Table 2). The trial results are not yet disclosed.
4.4 PDE4 inhibitors
The oral phosphodiesterase-4 (PDE4) inhibitor apremilast was approved for the treatment of moderate to severe plaque psoriasis [98]. However, apremilast has only modest efficacy with PASI75 rates clearly lower than biologics. Inhibition of PDE4 indirectly down regulates immune modulators, including TNFα, IFNγ, IL-17 and IL-23 [99]. Due to the potential adverse events associated with oral administration, the topical PDE4 inhibitors, crisaborole and roflumilast, are being investigated as an alternative treatment of psoriasis aiming to avoid systemic adverse effects (Table 2).
AN-2728 (crisaborole) ointment has been approved for the treatment of atopic dermatitis [100]. AN-2728 is a newer generation of PDE4 inhibitors [101]. Its binding mode to the catalytic site of PDE4 is distinct from traditional PDE4 inhibitors and can reduce pro-inflammatory cytokines TNFα, IL-2, IFNγ, and IL-5. In phase 2 studies to treat mild-to-moderate plaque-type psoriasis, AN-2728 ointment showed modest efficacy (40% of patients achieved a ≥ 2 grade improvement as assessed by the overall target Plaque Severity Score) [102]. Most adverse effects were mild to moderate.
The oral PDE4 inhibitor roflumilast has been approved by FDA for the treatment of chronic obstructive pulmonary disease (COPD) exacerbation since 2011 [103]. The topical roflumilast, in a high-water-content moisturizing cream base vehicle containing the cosmetic solvent ethoxydiglycol, is being investigated for the treatment of plaque psoriasis [104]. Its inhibitor affinity (IC50 values) is 25 to 300 folds more potent than either apremilast or crisaborole depending on PDE4 isoform analyzed [105]. In the phase 2b trial, approximately 85% of the enrolled patients had moderate-to-severe psoriasis and a generally similar percentage of patients in the roflumilast 0.3% group (31%) met the criterion for the PASI75 response at week 8 although differences in trial design do not allow to make direct comparisons [104, 105]. Oral apremilast has been associated with gastrointestinal adverse events of diarrhea and nausea, whereas topical roflumilast cream was associated with less than 1% of each of these events in this phase 2b trial. This may be a result of topical administration bypassing the gastrointestinal tract. Longer and larger trials are in progress to determine the durability and safety of roflumilast in psoriasis (Table 2).
4.5 AhR agonists
Tapinarof (also known as WBI-1001, GSK2894512, DMVT-505) is a naturally derived small molecule produced by bacterial symbionts of entomopathogenic nematodes [106]. Broad cellular profiling of tapinatof identified aryl hydrocarbon receptor (AhR) as a primary target [107]. Tapinarof activates the AhR pathway through direct binding. It was reported that AhR activation can modify transcriptional regulation of the immune system and, specifically, affect the differentiation of Th17 and Treg cells [108]. Tapinarof has been shown to inhibit IL-17A message expression by approximately 50% and robustly increase IL-22 levels [107]. Furthermore, 1% tapinarof cream can reduce imiquimod (IMQ)-induced skin inflammation and suppress IMQ-induced IL-17A and IL-17F gene expression in AhR-sufficient, but not AhR-deficient mice.
Topical 1.0% tapinarof met its primary endpoint in patients with mild-to-moderate psoriasis from a randomized double-blind placebo-controlled phase II trial [109]. The improvement in PGA at week 12 was 62.8% for patients randomized to tapinarof when compared with 13.0% for patients randomized to placebo (p < 0.0001). The adverse events observed in patients treated with tapinarof were all mild to moderate in intensity.
In 2018, GlaxoSmithKline (GSK) withdrew its phase III trial of tapinarof (GSK2894512) and sold mostly global rights of its Phase III-bound psoriasis candidate tapinarof to Dermavant Sciences [110]. On 9/30/2021, Dermavant Sciences disclosed final results from Phase III PSOARING 3 long-term extension study of tapinarof, a 1.0% once a daily, in patients with plaque psoriasis [111]. 58.2% (302/519) of patients with a PGA score ≥ 2 achieved a PGA score of 0 or 1. Moreover, 40.9% (312/763) of all patients achieved complete disease clearance (PGA score of 0). Those results demonstrate tapinarof’s continued improvement in efficacy beyond the 12-week pivotal studies. Treatment-emergent adverse events (TEAEs) were mostly mild to moderate, at application sites, and associated with a low discontinuation rate (5.4%). Incidence and severity of folliculitis and contact dermatitis remained stable with long-term use (up to 52 weeks) and were associated with low discontinuation rates (1.2% and 1.4%, respectively). The FDA accepted the New Drug Application submitted in May 2021, and assigned a Prescription Drug User Fee Act target action date in the second quarter of 2022.
5. Conclusion
A rapidly growing body of literature suggests that the IL-23/IL-17 axis is the major pathway that drives the chronic inflammation underlying psoriasis pathophysiology. The recent years have witnessed that superior clinical efficacy of IL-23/IL-17 pathway biologics in the systemic treatment of psoriasis brings to a major paradigm shift for the management of moderate-to-severe psoriasis. Nevertheless, lack of molecular targeted therapies remains for topical treatment of psoriasis.
With the rapid development of small molecule drugs for the topical treatment of psoriasis, molecular targeted therapies in the IL-23/IL17 axis have the potential to ascertain their role as effective and safe therapy. Although tapinarof and roflumilast are promising therapies in topical treatment of psoriasis, there are still considerable challenges in topical treatment. Many other topical therapeutic agents hold promise and warrant further investigation. Limitations of this chapter include a paucity of randomized controlled clinical trials for topical agents in the treatment of psoriasis, especially for most agents with none or only preliminary data available. Some studies report on a limited duration and a limited number of participants challenging generalizability to the clinic population. Much work is still required for the next breakthrough in the discovery of novel effective and safe topical therapy for psoriasis.
\n',keywords:"psoriasis, topical drug, TH17, IL-23, IL-17, small molecule inhibitor",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/80574.pdf",chapterXML:"https://mts.intechopen.com/source/xml/80574.xml",downloadPdfUrl:"/chapter/pdf-download/80574",previewPdfUrl:"/chapter/pdf-preview/80574",totalDownloads:44,totalViews:0,totalCrossrefCites:0,dateSubmitted:"November 27th 2021",dateReviewed:"January 17th 2022",datePrePublished:"February 23rd 2022",datePublished:null,dateFinished:"February 22nd 2022",readingETA:"0",abstract:"Psoriasis is a chronic inflammatory skin disorder. The prevalence of psoriasis is estimated at approximately 100 million people worldwide. In mild-to-moderate, as well as moderate-to-severe, psoriasis, 70–80% of patients start with topical agents and continue to use them with other active therapies. This group of patients can benefit from topical treatment with minimal systemic exposure. The expression levels of IL-23 and IL-17 are upregulated in psoriatic skin compared with non-lesional skin, associated with psoriasis pathogenesis. The skin epidermal proliferation and psoriasis are caused by overactive Th17 cells, which are promoted and stabilized by the activated IL-23 receptor, forming part of the positive feedback loop. FDA approved biologics in IL-23/IL-17 axis (ustekinumab, guselkumab, risankizumab, tildrakizumab, ixekizumab, secukinumab and brodalumab) demonstrated superior clinical efficacy in the systemic treatment of moderate-to-severe psoriasis, providing the clinical proof of concept of the IL-23/IL-17 axis as a major immune pathway underlying the pathophysiology of psoriasis. However, due to the large size and poor permeability into skin, biologics are not suitable to deliver via topical route. Current topical treatments of mild-to-moderate psoriasis are corticosteroids and vitamin D analogues, which have limited efficacy with significant side effects so that patients must avoid long-term use. This chapter reviews current molecular targeted therapeutics under development for topical treatment of psoriasis.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/80574",risUrl:"/chapter/ris/80574",signatures:"Suxing Liu, Di Li and Weikang Tao",book:{id:"11087",type:"book",title:"Psoriasis",subtitle:null,fullTitle:"Psoriasis",slug:null,publishedDate:null,bookSignature:"Associate Prof. Shahin Aghaei",coverURL:"https://cdn.intechopen.com/books/images_new/11087.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-376-4",printIsbn:"978-1-80355-375-7",pdfIsbn:"978-1-80355-377-1",isAvailableForWebshopOrdering:!0,editors:[{id:"64024",title:"Associate Prof.",name:"Shahin",middleName:null,surname:"Aghaei",slug:"shahin-aghaei",fullName:"Shahin Aghaei"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. IL-23/IL-17 axis is a major immune pathway in the development of psoriasis",level:"1"},{id:"sec_2_2",title:"2.1 Psoriasis is a TH17-driven disease",level:"2"},{id:"sec_3_2",title:"2.2 IL-23 stimulates TH17 cell survival and proliferation",level:"2"},{id:"sec_4_2",title:"2.3 IL-17 is a central proinflammatory effector cytokine in psoriasis",level:"2"},{id:"sec_6",title:"3. Clinical proof of concept of targeting the IL-23/IL-17 axis for the treatment of plaque psoriasis",level:"1"},{id:"sec_7",title:"4. New targeted therapeutics in development for topical treatment of psoriasis",level:"1"},{id:"sec_7_2",title:"4.1 RORγ antagonists",level:"2"},{id:"sec_8_2",title:"4.2 JAK inhibitors",level:"2"},{id:"sec_9_2",title:"4.3 DNMT inhibitors",level:"2"},{id:"sec_10_2",title:"4.4 PDE4 inhibitors",level:"2"},{id:"sec_11_2",title:"4.5 AhR agonists",level:"2"},{id:"sec_13",title:"5. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Griffiths CE, Barker JN. 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The New England Journal of Medicine. 2018;379(14):1313-1321. DOI: 10.1056/NEJMoa1806382'},{id:"B92",body:'Papp KA, Bissonnette R, Gooderham M, Feldman SR, Iversen L, Soung J, et al. Treatment of plaque psoriasis with an ointment formulation of the Janus kinase inhibitor, tofacitinib: A phase 2b randomized clinical trial. BMC Dermatology. 2016;16(1):15. DOI: 10.1186/s12895-016-0051-4'},{id:"B93",body:'FDA approves Opzelura. 2021. Available from: https://www.drugs.com/newdrugs/fda-approves-opzelura-ruxolitinib-cream-atopic-dermatitis-ad-5666.html [Accessed: October 22, 2021]'},{id:"B94",body:'Punwani N, Scherle P, Flores R, Shi J, Liang J, Yeleswaram S, et al. Preliminary clinical activity of a topical JAK1/2 inhibitor in the treatment of psoriasis. Journal of the American Academy of Dermatology. 2012;67:658-664. DOI: 10.1016/j.jaad.2011.12.018'},{id:"B95",body:'Ortiz-Ibanez K, Alsina MM, Munoz-Santos C. Tofacitinib and other kinase inhibitors in the treatment of psoriasis. Actas Dermo-Sifiliográficas. 2013;104(4):304-310. DOI: 10.1016/j.adengl.2013.03.002'},{id:"B96",body:'Banfield C, Scaramozza M, Zhang W, Kieras E, Page KM, Fensome A, et al. The safety, tolerability, pharmacokinetics, and pharmacodynamics of a TYK2/JAK1 inhibitor (PF-06700841) in healthy subjects and patients with plaque psoriasis. Journal of Clinical Pharmacology. 2018;58(4):434-447. DOI: 10.1002/jcph.1046'},{id:"B97",body:'Durect. DUR-928. 2021. Available from: https://www.durect.com/pipeline/dur-928/overview/ [Accessed: October 10, 2021]'},{id:"B98",body:'Vangipuram R, Alikhan A. Apremilast for the management of moderate to severe plaque psoriasis. Expert Review of Clinical Pharmacology. 2017;10(4):349-360. DOI: 10.1080/17512433.2017.1293519'},{id:"B99",body:'Li H, Zuo J, Tang W. Phosphodiesterase-4 inhibitors for the treatment of inflammatory diseases. Frontiers in Pharmacology. 2018;9:1048. DOI: 10.3389/fphar.2018.01048'},{id:"B100",body:'Pfizer. Pfizer receivers FDA approval for EUCRISA™ (crisaborole), a novel non-steroidal topical ointment for mild to moderate atopic dermatitis (Eczema). 2016. Available from: https://www.pfizer.com/news/press-release/press-release-detail/pfizer_receives_fda_approval_for_eucrisa_crisaborole_a_novel_non_steroidal_topical_ointment_for_mild_to_moderate_atopic_dermatitis_eczema. [Accessed: October 12, 2021]'},{id:"B101",body:'Akama T, Baker SJ, Zhang YK, Hernandez V, Zhou H, Sanders V, et al. Discovery and structure-activity study of a novel benzoxaborole anti-inflammatory agent (AN2728) for the potential topical treatment of psoriasis and atopic dermatitis. Bioorganic & Medicinal Chemistry Letters. 2009;19:2129-2132. DOI: 10.1016/j.bmcl.2009.03.007'},{id:"B102",body:'Moustafa F, Feldman SR. A review of phosphodiesterase-inhibition and the potential role for Phosphodiesterase-4 inhibitors in clinical dermatology. Dermatology Online Journal. 2014;20(5):1. DOI: 10.5070/D3205022608'},{id:"B103",body:'Oba Y, Lone NA. Efficacy and safety of roflumilast in patients with chronic obstructive pulmonary disease: A systematic review and meta-analysis. Therapeutic Advances in Respiratory Disease. 2012;7(1):13-24. DOI: 10.1177/1753465812466167'},{id:"B104",body:'Lebwohl MG, Papp KA, Gold LS, Gooderham MJ, Kircik LH, Draelos ZD. Trial of Roflumilast cream for chronic plaque psoriasis. The New England Journal of Medicine. 2020;383:229-239. DOI: 10.1056/NEJMoa2000073'},{id:"B105",body:'Milakovic M, Gooderham MJ. Phosphodiesterase-4 inhibition in psoriasis. Psoriasis. 2021;11:21-29. DOI: 10.2147/PTT.S303634'},{id:"B106",body:'Richardson WH, Schmidt TM, Nealson KH. Identification of an anthraquinone pigment and a hydroxystilbene antibiotic from Xenorhabdus luminescens. Applied and Environmental Microbiology. 1988;54(6):1602-1605. DOI: 10.1128/aem.54.6.1602-1605.1988'},{id:"B107",body:'Smith SH, Jayawickreme C, Rickard DJ, Nicodeme E, Bui T, Simmons C, et al. Tapinarof is a natural AhR agonist that resolves skin inflammation in mice and humans. The Journal of Investigative Dermatology. 2017;137(10):2110-2119. DOI: 10.1016/j.jid.2017.05.004'},{id:"B108",body:'Veldhoen M, Hirota K, Westendorf AM, Buer J, Dumoutier L, Renauld JC, et al. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature. 2008;453:106-109. DOI: 10.1038/nature06881'},{id:"B109",body:'Bissonnette R, Bolduc C, Maari C, Nigen S, Webster JM, Tang L, et al. Efficacy and safety of topical WBI-1001 in patients with mild to moderate psoriasis: Results from a randomized double-blind placebo-controlled, phase II trials. Journal of the European Academy of Dermatology and Venereology. 2012;26:1516-1521. DOI: 10.1111/j.1468-3083.2011.04332.x'},{id:"B110",body:'GSK. GSK sells psoriasis/Dermatitis candidate tapinarof to Dermavant. 2018. Available from: https://www.genengnews.com/topics/drug-discovery/gsk-sells-psoriasis-dermatitis-candidate-tapinarof-to-dermavant/ [Accessed: October 12, 2021]'},{id:"B111",body:'Dermavant. Dermavant showcases new long-term data from Phase 3 +-PSOARING 3 trial of tapinarof in patients with plaque psoriasis at the 30th EADV Virtual Congress. 2021. Available from: https://www.dermavant.com/dermavant-showcases-new-long-term-data-from-phase-3-psoaring-3-trial-at-the-30th-eadv-virtual-congress/ [Accessed: October 12, 2021]'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Suxing Liu",address:"lius@eternitybioscience.com",affiliation:'
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The applications of this research cover many related fields, such as biotechnology and medicine, where, for example, Bioinformatics contributes to faster drug design, DNA analysis in forensics, and DNA sequence analysis in the field of personalized medicine. Personalized medicine is a type of medical care in which treatment is customized individually for each patient. Personalized medicine enables more effective therapy, reduces the costs of therapy and clinical trials, and also minimizes the risk of side effects. Nevertheless, advances in personalized medicine would not have been possible without bioinformatics, which can analyze the human genome and other vast amounts of biomedical data, especially in genetics. The rapid growth of information technology enabled the development of new tools to decode human genomes, large-scale studies of genetic variations and medical informatics. 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Recently, bioinspired systems have been successfully employing biomechanics to develop and improve assistive technology and rehabilitation devices. The research topic "Bioinspired Technology and Biomechanics" welcomes studies reporting recent advances in bioinspired technologies that contribute to individuals\' health, inclusion, and rehabilitation. 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