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JAK-STAT Inhibitors in Atopic Dermatitis from Pathogenesis to Clinical Trials Results

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JAK-STAT Inhibitors in Atopic Dermatitis from Pathogenesis to Clinical Trials Results microorganisms Review JAK-STAT Inhibitors in Atopic Dermatitis from Pathogenesis to Clinical Trials Results Krzysztof Szalus, Magdalena Trzeciak * and Roman J. Nowicki Department of Dermatology, Venereology and Allergology, Medical University of Gdansk, 80-214 Gda´nsk,Poland; [email protected] (K.S.); [email protected] (R.J.N.) * Correspondence: [email protected]; Tel.: +48-58-5844010 Received: 24 September 2020; Accepted: 3 November 2020; Published: 6 November 2020 Abstract: A common disease worldwide is known as atopic dermatitis (AD), named also as atopic eczema, which is a chronic recurrent complex inflammatory skin disorder. It affects 2–10% of the adult population and up to 20% of the pediatric population. The clinical AD picture appears in typically localized eczema and dry skin, and is dominated by a persistent pruritus followed by sleep disturbances. AD strongly impacts on the quality of life of AD patients and their families as well as on social and economic aspects. The pathogenesis of the disease is complex and consists of multiple interactions between immunological disturbances, skin barrier defect, and microbial dysbiosis with environmental influences. The treatment of AD reflects the pathogenetic disorders, starting from basic emollient therapy, and goes to topical anti-inflammatory regimens followed by phototherapy, systemic immunosuppressive drugs, and new biologic immunomodulators. This paper will thus summarize the novel collection of biological treatment JAK-STAT inhibitors dedicated to AD. Keywords: atopic dermatitis; JAK-STAT; abrocitinib; baricitinib; upadacitinib; tofacitinib; delgocitinib; ruxolitinib; cerdulatinib; gusacitinib 1. Introduction Atopic dermatitis (AD) as an inflammatory disease that mostly affects children and less adults. The prevalence of this is still rising and affects between 10% and 20% of children in the global population, starting in early childhood. The majority of symptoms appear before the first year of life in about 60% of children. Another 30% with AD will exhibit their first symptoms between their first and fifth year of life and the minority (10%) after their sixth year of life [1]. Adult population with AD prevalence oscillates between 2.1% to 4.9% globally [2]. There is no specific markers to indicate while diagnosing AD, so the long, sometimes troublesome diagnostic process is based on clinical symptoms following the criteria of Hanifin and Rajka [3] and medical records of the patient after exclusion of other inflammatory mediated diseases (Figure1). Clinical picture beside pruritus and dry skin manifests as exematouse lesions localized mainly in flexures, but it may spread through the whole body. In infants, thee extensor side is typical (Figure2). The treatment of AD reflects the pathogenetic disorders. Current management of AD is a combination of basic emollient therapy goes to topical anti-inflammatory regimens followed by phototherapy and in the case the other treatment fails, moving to systemic immunosuppressive drugs. Although many schemes depend on the age and severity of the disease, we are still lacking success in the treatment of moderate and severe AD. The need for novel treatments with a steroid sparing effect, to encompass the potential side effects of topical corticosteroids over the long-term use is crucial. Thus, there is a need to search for better solutions of treatment, control, healing, and prevent the disease and its consequences like so called “atopic march”. Better understanding of AD pathogenesis, its immunological mechanisms, a variety of monoclonal antibodies targeting cytokines, and small molecules interfering with intracellular signaling Microorganisms 2020, 8, 1743; doi:10.3390/microorganisms8111743 www.mdpi.com/journal/microorganisms Microorganisms 2020, 8, 1743 2 of 14 Microorganisms 2020, 8, x FOR PEER REVIEW 2 of 15 Microorganisms 2020, 8, x FOR PEER REVIEW 2 of 15 pathways havehave beenbeen developeddeveloped and and let let us us create create novel novel drugs drugs that that do do not not focus focus on on a singlea single pathological patholog- pathways have been developed and let us create novel drugs that do not focus on a single patholog- pathway of the disease, but more complex molecular interactions that drive AD. We also observed new icalical pathway pathway ofof thethe disease,disease, butbut moremore complexcomplex molecular interactionsinteractions thatthat drivedrive AD.AD. WeWe also also ob- ob- possible and effective trends of treating atopic dermatitis mostly by focusing on a personal conception servedserved new new possible possible andand effectiveeffective trendstrends of treating atopic dermatitisdermatitis mostlymostly byby focusingfocusing on on a a per- per- ofsonalsonal the con patient’sconceptionception disease of of the the like patient’spatient’s AD immuno diseasedisease/ genolike AD/phenotypes. immuno/geno/phenotypes. FigureFigure 1. 1. DiDifferential Differentialfferential diagnosisdiagnosis ofof atopicatopic dermatitisdermatitis (AD). Main potential potential diseases diseases that that can can confuse confuse ADAD diagnosis diagnosis areare includedincluded inin thethe table.table.table. Many different different options dodo make make thisthis an an easy easy way way to to reach reach finalfinalfinal diagnosis. diagnosis. Figure 2. Typical location and morphology of atopic eczema. Photos show typical location of skin Figure 2.2. Typical location and morphologymorphology of atopicatopic eczema.eczema. Photos show typical location of skin lesions in children. lesions inin children.children. 2. Pathogenesis of Atopic Dermatitis 2. Pathogenesis of Atopic Dermatitis AD pathogenesis is complex (Figure 3) and includes disorders in skin barrier, immunology, and AD pathogenesis pathogenesis is is complex complex (Figure (Figure 3)3 )and and includes includes disorders disorders in skin in skin barrier, barrier, immunology, immunology, and skin microbiota. AD development also depends on environmental and personal factors. andskin skinmicrobiota. microbiota. AD development AD development also alsodepends depends on environmental on environmental and andpersonal personal factors. factors. Microorganisms 2020, 8, x FOR PEER REVIEW 3 of 15 Microorganisms 2020, 8, 1743 3 of 14 FigureFigure 3. 3.AD AD pathogenesis. pathogenesis.A A compoundcompound processprocess in the picture unveiled the the combined combined pathogenesis pathogenesis ofof AD AD that that leads leads to to the the acute acute phase phase ofof thethe disease.disease. The picture is is simplified simplified to to understand understand the the influence influence ofof many many di differentfferent factorsfactors including environment environment on on AD AD focus. focus. Key Key (+: stimulation, (+: stimulation, ↑: increase,: increase, ↓: " :decrease) decrease).. # 2.1.2.1. Skin Skin Barrier Barrier Defect Defect MolecularMolecular defects, defects, which which take take place place within within the the dermal dermal layers layers manifest manifest themselves themselves as as dysregulation dysregula- oftion cornified of cornified envelope envelope (CE) proteins, (CE) proteins, stratum stratum corneum corneum lipids, lipids, tight junctions,tight junctions, and overreaction and overreaction of serine of proteaseserine protease [4], explain [4], explain many ADmany symptoms. AD symptoms. Filaggrin Filaggrin (FLG) (FLG) is the is bestthe best searched searched cornified cornified envelope enve- proteinlope protein in AD pathogenesisin AD pathogenesis and when and it when acts properly, it acts properly, it is a substrate it is a substrate for natural for moistening natural moistening factor. It is obviousfactor. thatIt is theobvious lack ofthat FLG the results lack of in FLG skin results dryness, in skin but notdrynes onlys, asbut filaggrin not only mutations as filaggrin are mutations associated withare severeassociated AD with course, severe concomitant AD course, asthma, concomitant and elevated asthma, IgE and level elevated [5]. FurtherIgE level consequence [5]. Further conse- of FLG disorderquence isof incorrectFLG disorder skin is pH, incorrect which skin creates pH, unfavorable which creates conditions unfavorable for lipidconditions synthesizing for lipid enzymes.synthe- Thesizing decreased enzymes. expression The decreased of FLG expression and the CE of proteins FLG and is the the CE eff ectproteins of gene is the mutations effect of as gene well mutations as chronic inflammationas well as chronic in the atopicinflammation skin [6]. in Aside the atopic from diskinfferent [6]. Aside expressions from different of cornified expressions envelope of proteins cornified like FLG,envelope lorikrin proteins (LOR), like cornulin, FLG, lorikrin (CRNN), (LOR), repetin cornulin, (RPTN) (CRNN), and small repetin proline-rich (RPTN) and proteins small proline (SPRRs)-rich [7 ], theproteins stratum (SPRRs) corneum [7], is the deprived stratum of corneum intracellular is deprived lipids likeof intracellular ceramides lipids [8]. One like of ceramides the mechanisms [8]. One is connectedof the mechanisms with the maturing is connected of lamellar with the bodies maturing [9]. of The lamellar skin barrier bodies defect [9]. The is recognizedskin barrier indefect normal is skinrecognized without in the normal lesions skin and wi withinthout the lesionally lesions changedand within skin lesionally regions changed in AD patients skin regions [10]. in Epidermal AD pa- barriertients dysfunction[10]. Epidermal results barrier in increased dysfunction permeability,
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