Janus Kinase Inhibitors in Dermatology: Part 2: Applications in Psoriasis, Atopic Dermatitis, and Other Dermatoses

array:25 ["pii" => "S1578219021001682" "issn" => "15782190" "doi" => "10.1016/j.adengl.2021.05.008" "estado" => "S300" "fechaPublicacion" => "2021-07-01" "aid" => "2587" "copyright" => "AEDV" "copyrightAnyo" => "2021" "documento" => "article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "rev" "cita" => "Actas Dermosifiliogr. 2021;112:586-600" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "Traduccion" => array:1 [ "es" => array:20 [ "pii" => "S0001731021000065" "issn" => "00017310" "doi" => "10.1016/j.ad.2020.12.006" "estado" => "S300" "fechaPublicacion" => "2021-07-01" "aid" => "2587" "copyright" => "AEDV" "documento" => "article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "rev" "cita" => "Actas Dermosifiliogr. 2021;112:586-600" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "es" => array:13 [ "idiomaDefecto" => true "cabecera" => "REVISIÓN" "titulo" => "Inhibidores de JAK: usos en dermatología. Parte 2: aplicaciones en psoriasis, dermatitis atópica y otras dermatosis" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "586" "paginaFinal" => "600" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Janus Kinase Inhibitors in Dermatology: Part 2: Applications in Psoriasis, Atopic Dermatitis, and Other Dermatoses" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figura 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1650 "Ancho" => 2917 "Tamanyo" => 276752 ] ] "descripcion" => array:1 [ "es" => "Vía de señalización IL-4/IL-13/JAK/STAT y vía SYK en dermatitis atópica. Se representan en la imagen los diferentes inhibidores de JAK y los inhibidores duales de JAK/SYK en dermatitis atópica. Las funciones biológicas de IL-4 e IL-13 son mediadas por su unión a las subunidades IL-4Rα e IL-13Rα1 de los correspondientes receptores. La IL-4 se une a un receptor de tipo I que comprende la IL-4Rα y la cadena γ del receptor de citocinas o bien a un receptor tipo II configurado por IL-4Rα e IL-13R α1. Este último es el receptor principal de IL-13. La IL-5 producida como consecuencia de la polarización Th2 se une a la subunidad IL-5Rα de su receptor, formando un complejo con una subunidad de señalización compartida, la cadena β, e induciendo la fosforilación de JAK1/JAK2 y la activación de STAT1, STAT3, y STAT5. La SYK se une mediante sus dominios SH2 característicos a motivos de activación de inmunorreceptores basados en tirosina (ITAM) difosforilados, situados en la región citoplasmática de diversos receptores inmunológicos, como por ejemplo los receptores de células T, B, NK o los diversos receptores para la fracción constante de inmunoglobulina (Fc) localizados en neutrófilos, mastocitos, macrófagos, células dendríticas y otras estirpes del sistema inmune. Como resultado de esta interacción se activan otras proteínas que transmiten las señales «aguas abajo». Dibujo creado con la ayuda de Biorender.com." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "C. García-Melendo, X. Cubiró, L. Puig" "autores" => array:3 [ 0 => array:2 [ "nombre" => "C." "apellidos" => "García-Melendo" ] 1 => array:2 [ "nombre" => "X." "apellidos" => "Cubiró" ] 2 => array:2 [ "nombre" => "L." 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B, Firm cutaneous leishmaniasis papules on the palm of a patient coinfected with visceral leishmaniasis and human immunodeficiency virus. C, Hyperpigmented macules in the neck area. D, Hypopigmented macules as a manifestation of post-kala-azar dermal leishmaniasis in a 7-year-old boy. The diagnosis was established by molecular techniques, as the biopsy was negative." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "I. Abadías-Granado, A. Diago, P.A. Cerro, A.M. Palma-Ruiz, Y. Gilaberte" "autores" => array:5 [ 0 => array:2 [ "nombre" => "I." "apellidos" => "Abadías-Granado" ] 1 => array:2 [ "nombre" => "A." "apellidos" => "Diago" ] 2 => array:2 [ "nombre" => "P.A." "apellidos" => "Cerro" ] 3 => array:2 [ "nombre" => "A.M." "apellidos" => "Palma-Ruiz" ] 4 => array:2 [ "nombre" => "Y." "apellidos" => "Gilaberte" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1578219021001712?idApp=UINPBA000044" "url" => "/15782190/0000011200000007/v1_202107020822/S1578219021001712/v1_202107020822/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S1578219021001669" "issn" => "15782190" "doi" => "10.1016/j.adengl.2021.05.007" "estado" => "S300" "fechaPublicacion" => "2021-07-01" "aid" => "2584" "copyright" => "AEDV" "documento" => "article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "rev" "cita" => "Actas Dermosifiliogr. 2021;112:573-85" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "Review" "titulo" => "Subungual Melanocytic Lesions: Key Clinical and Pathologic Concepts and Biopsy Techniques" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "573" "paginaFinal" => "585" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Lesiones melanocíticas subungueales: claves clínico-patológicas y técnicas de biopsia" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1894 "Ancho" => 2500 "Tamanyo" => 271527 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0020" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Technique of nail apparatus biopsy. Punch biopsies and longitudinal elliptical biopsy of the bed (pink), punch biopsies and transverse elliptical biopsies of the nail matrix (blue), shave biopsy of the nail bed (green), and longitudinal excision biopsy (yellow)." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "E. Ríos-Viñuela, L. Nájera-Botello, L. Requena, E. Nagore, C. Requena" "autores" => array:5 [ 0 => array:2 [ "nombre" => "E." "apellidos" => "Ríos-Viñuela" ] 1 => array:2 [ "nombre" => "L." "apellidos" => "Nájera-Botello" ] 2 => array:2 [ "nombre" => "L." "apellidos" => "Requena" ] 3 => array:2 [ "nombre" => "E." "apellidos" => "Nagore" ] 4 => array:2 [ "nombre" => "C." "apellidos" => "Requena" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1578219021001669?idApp=UINPBA000044" "url" => "/15782190/0000011200000007/v1_202107020822/S1578219021001669/v1_202107020822/en/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "Review" "titulo" => "Janus Kinase Inhibitors in Dermatology: Part 2: Applications in Psoriasis, Atopic Dermatitis, and Other Dermatoses" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "586" "paginaFinal" => "600" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "C. Garcia-Melendo, X. Cubiró, L. Puig" "autores" => array:3 [ 0 => array:4 [ "nombre" => "C." "apellidos" => "Garcia-Melendo" "email" => array:1 [ 0 => "cris.garciamelendo@gmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "X." "apellidos" => "Cubiró" ] 2 => array:2 [ "nombre" => "L." "apellidos" => "Puig" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Dermatología, Hospital de la Santa Creu i Sant Pau, Barcelona, Universitat Autònoma de Barcelona, Barcelona, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Inhibidores de JAK: usos en dermatología. Parte 2: aplicaciones en psoriasis, dermatitis atópica y otras dermatosis" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1650 "Ancho" => 2917 "Tamanyo" => 276752 ] ] "descripcion" => array:1 [ "en" => "IL-4/IL-13/JAK/STAT signaling pathway and SYK pathway in atopic dermatitis. The figure shows various JAK inhibitors and dual JAK/SYK inhibitors in atopic dermatitis. The biological functions of IL-4 and IL-13 are mediated by their binding to the subunits IL-4Rα and IL-13Rα1 of the corresponding receptors. IL-4 binds to a type 1 receptor that includes IL-4Rα and the γ chain of the cytokine receptor or a type 2 receptor configured by IL-4Rα and IL-13R α1. The latter is the main IL-13 receptor. IL-5 produced as a result of polarization of type 2 helper T cells binds to the IL-5Rα subunit of its receptor to form a complex with a shared signaling subunit, the β chain, and induce phosphorylation of JAK1/JAK2 and activation of STAT1, STAT3, and STAT5. Via its SH2 domains, SYK binds to diphosphorylated immunoreceptor tyrosine-based activation motifs (ITAM) in the cytoplasm of various immune receptors, such as T-, B-, NK-cell receptors or the various receptors for the constant fraction of immunoglobulin (Fc) in neutrophils, mastocytes, macrophages dendritic cells, and other strains of the immune system. This interaction results in the activation of other proteins that transmit downstream signals. Figure generated with the assistance of Biorender.com." ] ] ] "textoCompleto" => "IntroductionPart 1 of this review provided a detailed description of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) intracellular signaling pathway. The potential role of JAK inhibitors in the treatment of various dermatologic diseases was highlighted, with emphasis on available evidence for vitiligo and alopecia areata.Here, in Part 2, we review pathogenesis and the role of the JAK/STAT pathway in psoriasis and atopic dermatitis, as well as in other skin conditions such as hidradenitis, dermatomyositis, and graft-versus-host disease.PsoriasisThe interleukin (IL) 23/IL-17 (IL-23/IL-17) axis is currently considered the main pathogenic pathway in psoriasis. However, several cytokines play a role in this disease, and some transmit their signal after binding to the corresponding receptors via the JAK/STAT pathway. These include interferon (IFN) γ, IFN-α, IL-2, IL-6, IL-12, IL-13, IL-19, IL-20, IL-21, IL-22, and IL-23. Tumor necrosis factor (TNF) α and other cytokines, such as IL-17, IL-8, and those of the IL-1 family (IL-1, IL-18, IL-36, and IL-38), do not directly activate the JAK/STAT pathway, although their activity can be suppressed indirectly through inhibition of the JAK/STAT pathway.<a class="elsevierStyleCrossRefs" href="#bib0540">1–3</a>JAK signaling has been shown to be overregulated, with increased expression of STAT1 and STAT3 in lesional psoriatic skin when compared with healthy skin.<a class="elsevierStyleCrossRefs" href="#bib0555">4–6</a>STAT1 is responsible for the transduction of type 1 IFN signals (α and β) and type 2 signals (γ) via a JAK1/JAK2–dependent mechanism, leading to production of multiple proinflammatory mediators and activation and maturation of dendritic cells with stimulation of type 1 helper T cells (TH1) and TH17.<a class="elsevierStyleCrossRefs" href="#bib0570">7,8</a>STAT3 is involved in the induction and differentiation of TH17 cells via activation of JAK2/TYK2 induced by IL-23.<a class="elsevierStyleCrossRef" href="#bib0580">9</a> In addition, TH17 cells can produce IL-22, which is responsible for epidermal hyperplasia and production of antimicrobial peptides by keratinocytes.<a class="elsevierStyleCrossRefs" href="#bib0545">2,10</a> STAT3 also participates in the proliferation of keratinocytes via IL-6–induced activation of JAK1/JAK2 or JAK1/TYK2<a class="elsevierStyleCrossRefs" href="#bib0590">11,12</a> and is indirectly activated by IL-17 through induction of IL-19 and/or IL-36 by keratinocytes.<a class="elsevierStyleCrossRef" href="#bib0600">13</a>Oral TofacitinibTofacitinib (Xeljanz, Pfizer) mainly inhibits JAK1 and JAK3. It has been approved by the United States Food and Drug Administration (FDA) for the treatment of adults with psoriatic arthritis and for the treatment of moderate to severe rheumatoid arthritis at doses of 5mg twice daily.<a class="elsevierStyleCrossRef" href="#bib0605">14</a> It was recently approved for the treatment of polyarticular juvenile idiopathic arthritis in children aged ≥2 years,<a class="elsevierStyleCrossRef" href="#bib0610">15</a> as well as for treatment of ulcerative colitis at doses of 10mg twice daily for 8 weeks and subsequently at 5mg twice daily.<a class="elsevierStyleCrossRefs" href="#bib0605">14,16</a> Tofacitinib has proven effective in moderate to severe psoriasis in phase 2 and 3 trials.In a study of 197 patients, treatment with tofacitinib 2mg, 5mg, and 15mg twice daily achieved a Psoriasis Area and Severity Index 75 (PASI75) response rate of 25%, 41%, and 67%, respectively, at 12 weeks, compared with 2% for placebo. PASI90 was achieved at 12 weeks by 22% of those who received tofacitinib.<a class="elsevierStyleCrossRef" href="#bib0620">17</a>A phase 3 trial of 1106 patients with plaque psoriasis and PASI ≥12 revealed the noninferiority of tofacitinib 10mg/12h to subcutaneous etanercept 50mg at week 12, with a similar rate of adverse events in each group.<a class="elsevierStyleCrossRef" href="#bib0625">18</a>Two phase 3 trials (OPT Pivotal 1 [901 patients] and OPT Pivotal 2 [960 patients]<a class="elsevierStyleCrossRef" href="#bib0630">19</a>), tofacitinib 10mg/12h was more efficacious than 5mg/12h from week 16 onward, with a greater PASI75 response rate between week 16 and week 28. Among the patients who reached PASI75 at week 16, the response was maintained at 52 weeks in 74.1% of the 5mg/12h group and 79.4% of the 10mg/12h group, and most continued to do so at 24 months.<a class="elsevierStyleCrossRef" href="#bib0635">20</a> In addition, at 16 weeks of treatment, both doses led to an improvement in ungual psoriasis, pruritus (the difference was evident 1 day after initiation of treatment), and the Dermatology Life Quality Index. The improvement was maintained at week 52.<a class="elsevierStyleCrossRefs" href="#bib0640">21,22</a> Another phase 3 trial achieved an American College of Rheumatology (ACR) 20 response at week 16 in all patients with psoriatic arthritis treated with tofacitinib (5mg/12h or 10mg/12h) and an ACR50 or ACR70 in more than half. The responses were maintained at week 52.<a class="elsevierStyleCrossRef" href="#bib0650">23</a>Most adverse effects were mild or moderate. In the tofacitinib groups, 12 patients had herpes zoster, although the most frequent adverse effect was nasopharyngitis.<a class="elsevierStyleCrossRef" href="#bib0630">19</a> Two patients treated with tofacitinib 10mg every 12h in OPT Pivotal 1 had severe infections (appendicitis, pneumonia, and pyelonephritis), whereas 3 patients who received tofacitinib 5mg every 12h in OPT Pivotal 2 had severe infections (pneumonia, herpes zoster, erysipelas). Both studies reported an increase in cholesterol and creatine phosphokinase and reduced hemoglobin.The adverse effects of tofacitinib are similar at 5mg and 10mg, with the most frequent being mild cytopenia, upper respiratory tract infections, headache, urinary tract infection, and diarrhea.<a class="elsevierStyleCrossRefs" href="#bib0620">17,19,20,24</a> In October 2015, the FDA refused to approve tofacitinib for treatment of moderate to severe plaque psoriasis, alleging that more studies were necessary on long-term safety.<a class="elsevierStyleCrossRef" href="#bib0660">25</a>Topical TofacitinibTopical tofacitinib could be an alternative therapy in mild to moderate plaque psoriasis. It has a favorable safety profile, although the improvement reported in published studies is slight. In a phase 2a study of 71 patients, the authors reported promising results with tofacitinib ointment 2% every 12hours. The percentage change in the Target Plaque Severity Score at week 4 with respect to baseline was statistically significant with tofacitinib ointment compared with the vehicle (minimum mean square, −54.4% vs. −41.5%, respectively).<a class="elsevierStyleCrossRef" href="#bib0665">26</a> A subsequent multicenter randomized study including 435 patients who received tofacitinib ointment 1% and 2% revealed greater efficacy than the vehicle for treatment of psoriasis at week 8 (Physician's Global Assessment [PGA] 0/1 in 18.6% of patients for tofacitinib 2% every 24hours and 22.5% for tofacitinib 2% every 12hours), although not at week 12. Reactions were observed at the application site in 8.1% of patients, although the highest incidence recorded for patients who received vehicle.<a class="elsevierStyleCrossRef" href="#bib0670">27</a>Topical RuxolitinibThe JAK1/2 inhibitor ruxolitinib has been assessed as topical treatment for psoriasis. In a phase 2 clinical trial, 29 patients were randomized to receive ruxolitinib cream 0.5% or 1% once daily or 1.5% twice daily for 28 days, vehicle, or an active comparator (calcipotriene cream 0.005% or betamethasone dipropionate 0.05%). Treatment with ruxolitinib cream 1% and 1.5% was safe, well tolerated, and effective, with reduced plaque thickness, erythema, scaling, and lesion size compared with the vehicle (reduction of 53% in the treatment groups vs. 32% in the vehicle group). No significant differences in efficacy were found between ruxolitinib and the active comparators.<a class="elsevierStyleCrossRef" href="#bib0675">28</a>Oral BaricitinibBaricitinib (Olumiant, Lilly) is a JAK1/2 inhibitor that has been approved by the FDA<a class="elsevierStyleCrossRef" href="#bib0680">29</a> and the European Medicines Agency (EMA)<a class="elsevierStyleCrossRef" href="#bib0685">30</a> for the treatment of moderate to severe rheumatoid arthritis at recommended doses of 4mg/d. It was recently approved for the treatment of moderate to severe atopic dermatitis.<a class="elsevierStyleCrossRef" href="#bib0685">30</a>Baricitinib was studied in a phase 2b trial for treatment of moderate to severe plaque psoriasis in 271 patients. The PASI75 at week 12 was significantly higher for the groups treated with 8mg and 10mg once daily than for placebo (42.9%, 54.1%, and 16.1%, respectively). The most common adverse effects were infection, with an incidence rate of 26.5% in the placebo group and 21.5% in the baricitinib groups, the most common being nasopharyngitis.<a class="elsevierStyleCrossRef" href="#bib0690">31</a>Oral AbrocitinibAbrocitinib (Pfizer) is a JAK1 inhibitor that was assessed for the treatment of moderate to severe psoriasis in a phase 2 trial lasting 12 weeks, in which 59 patients were randomly assigned to receive 200mg/24h, 400mg/24h, 200mg/12h, or placebo for 4 weeks. At week 4, the percentage of patients who achieved PASI75 was 17% for the placebo and 200mg/24h groups, 50% for the 400mg/24h group, and 60% for the 200mg/12h group. More laboratory abnormalities (low neutrophil, platelet, and reticulocyte counts) were observed in the 200mg/12h group, although no associated bleeding or severe infections were recorded.<a class="elsevierStyleCrossRef" href="#bib0695">32</a>Oral SolcitinibA dose-dependent improvement in psoriasis was recorded with solcitinib (GlaxoSmithKline), a JAK1 inhibitor that was assessed in a phase 2 trial. The study population comprised 60 patients, of whom 13% achieved PASI75 at 100mg/d, 25% at 200mg/d, 57% at 400mg/d, and 0% with placebo.<a class="elsevierStyleCrossRef" href="#bib0700">33</a>Oral Itacitinib AdipateThe JAK1 inhibitor itacitinib adipate (Incyte Corporation) led to a significant improvement in patients with moderate to severe psoriasis in a phase 2 trial including 50 patients and lasting 12 weeks. At 1 month, PASI75 was achieved by 0%, 11.1%, 0%, 22.2%, and 27.7% in the placebo, 100mg/24h, 200mg/24h, 200mg/12h, and 600mg/24h groups, respectively. The only significant differences with placebo were observed in the itacitinib 600mg/d group.<a class="elsevierStyleCrossRef" href="#bib0705">34</a>Oral PeficitinibPeficitinib (Smyraf, Astellas Pharma Inc.) is a pan-JAK inhibitor that has been approved in Japan for treatment of rheumatoid arthritis<a class="elsevierStyleCrossRef" href="#bib0710">35</a> that proved efficacious in a phase 2 trial including 124 patients with moderate to severe plaque psoriasis. Patients received active treatment (10mg, 25mg, 60mg, 100mg twice daily or 50mg once daily) or placebo. The mean improvement in PASI and body surface area with respect to baseline was significantly better in all treatment groups than in the placebo group at 6 weeks. The difference was dose-dependent.<a class="elsevierStyleCrossRef" href="#bib0715">36</a>TYK2 InhibitorsCurrent studies focus on TYK2 inhibitors for the treatment of moderate to severe psoriasis.The percentage of patients who reached PASI75 at 12 weeks in a phase 2 trial (267 patients) was significantly greater with deucravacitinib (a TYK2 inhibitor, Bristol-Myers Squibb) than with placebo (39% at 3mg/24h, 69% at 3mg/12h, 67% at 6mg/12h, and 75% at 12mg/24h vs. 7% in the placebo group). The PASI90 response rate was 43% at 12 weeks, and the PASI100 response rate was 25%.<a class="elsevierStyleCrossRef" href="#bib0720">37</a> The ongoing phase 3 trials with this drug (NCT04036435,<a class="elsevierStyleCrossRef" href="#bib0725">38</a> NCT03924427<a class="elsevierStyleCrossRef" href="#bib0730">39</a>) include one in which it is compared with apremilast (NCT03611751<a class="elsevierStyleCrossRef" href="#bib0735">40</a>).Brepocitinib (Pfizer) is a potent TYK2/JAK1 inhibitor that is being evaluated for treatment of psoriasis. In a phase 1 trial, 30 patients with moderate to severe plaque psoriasis received 30mg or 100mg orally or placebo once daily for 28 days. A PGA 0/1 response was achieved in 57.1%, 100%, and 0% of cases, respectively.<a class="elsevierStyleCrossRef" href="#bib0740">41</a> Topical application of brepocitinib is currently being tested in a phase 2b trial in patients with mild to moderate psoriasis (NCT03850483<a class="elsevierStyleCrossRef" href="#bib0745">42</a>).Finally, another TYK2 inhibitor (PF-06826647, Pfizer) is being investigated for moderate to severe psoriasis in a phase 2 trial (NCT03895372<a class="elsevierStyleCrossRef" href="#bib0750">43</a>).Atopic DermatitisAtopic dermatitis is an inflammatory skin disease with a TH2-polarized immune response in its acute phase. The JAK/STAT pathway plays a key role in the dysregulation of the immune response in atopic dermatitis, including overregulation of TH2, activation of eosinophils, suppression of regulatory T cells, and maturation of B cells, with differentiation to plasma cells and secretion of immunoglobulin (Ig) E, which binds to cutaneous mastocytes and leads to release of histamine. Similarly, the TH2 response leads to release of proinflammatory cytokines and proangiogenic factors by epidermal cells.Atopic dermatitis is associated with an increase in signaling via JAK1, JAK2, JAK3, and TYK2<a class="elsevierStyleCrossRef" href="#bib0755">44</a> (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). JAK1, JAK3, and STAT6 are components of IL-4 signaling that are critical for TH2 cell differentiation<a class="elsevierStyleCrossRefs" href="#bib0760">45–47</a> and production of IL-4, IL-5, IL-10, and IL-13. STAT6 regulates the genes involved in TH2 cells and B-cell differentiation, switching from IgG to IgE, and production of class II major histocompatibility complex molecules. Various STAT6 polymorphisms have been associated with greater susceptibility to atopic dermatitis and high IgE levels.<a class="elsevierStyleCrossRef" href="#bib0775">48</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>The IL-4/IL-13/JAK/STAT pathway<a class="elsevierStyleCrossRef" href="#bib0780">49</a> is important for the integrity of the skin barrier. Suppression by nonselective JAK inhibitors of STAT3 activation induced by IL-4/IL-13 has been shown to improve barrier function, thus promoting production of filaggrin and loricrin.<a class="elsevierStyleCrossRef" href="#bib0785">50</a> Furthermore, IL-4 and IL-13 play a role in pruritus through their interaction with IL-4Rα and JAK1 in sensory neurons.<a class="elsevierStyleCrossRef" href="#bib0790">51</a>Factors other than IL-4 are important for differentiation of TH2. Thymic stromal lymphopoietin (TSLP) promotes TH2 cell differentiation, activates natural killer cells and basophils, and affects maturation of B cells. TSLP binds to a heterodimer composed of a TSLP receptor and an IL-7α receptor and induces phosphorylation of JAK1 and JAK2, leading to activation of STAT1, STAT3, and STAT5.<a class="elsevierStyleCrossRef" href="#bib0795">52</a>The spleen tyrosine kinase (SYK) pathway is also involved in the pathogenesis of atopic dermatitis. SYK is a cytoplasmic tyrosine kinase that is involved in signaling of proinflammatory cytokines and production of CCL20, which attracts TH17 cells to the skin<a class="elsevierStyleCrossRefs" href="#bib0800">53,54</a> (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Inhibition of SYK suppresses this activation and has an anti-inflammatory effect, which may be synergetic with concomitant inhibition of JAK. Favorable results have been reported for some dual inhibitors used to treat atopic dermatitis.Oral TofacitinibAn open-label study of 6 patients treated with tofacitinib 5mg once or twice daily, in addition to topical treatment, revealed a 36.6% reduction in the Scoring Atopic Dermatitis (SCORAD) score at weeks 8 to 12, and of 12% at week 29, with no remarkable adverse effects.<a class="elsevierStyleCrossRef" href="#bib0810">55</a>Topical TofacitinibApplication of topical tofacitinib 2% (20mg/g) every 12h in 69 patients with mild to moderate atopic dermatitis for 4 weeks led to an 81.7% reduction in the Eczema Area and Severity Index (EASI) score after 4 weeks, compared with 29.9% in patients receiving placebo. The Investigator Global Assessment (IGA), body surface area, and pruritus also improved from the first week of treatment.<a class="elsevierStyleCrossRef" href="#bib0815">56</a>Oral BaricitinibBaricitinib (Olumiant, Lilly) has been evaluated in a phase 2 trial and in 2 phase 3 trials for treatment of moderate to severe atopic dermatitis.Baricitinib was used concomitantly with topical triamcinolone 0.1% for 16 weeks in a phase 2 trial with 124 patients.<a class="elsevierStyleCrossRef" href="#bib0820">57</a> Severity of atopic dermatitis improved significantly in those who received 2mg and 4mg compared with placebo, with a rapid improvement in pruritis during the first week and in health-related quality of life. In the group treated with baricitinib 4mg, 61% of patients achieved an EASI50 response at 16 weeks compared with 37% in the placebo group.In 2 phase 3 studies in adults (BREEZE-AD1 [624 patients] and BREEZE-AD2 [615 patients), baricitinib improved the severity of atopic dermatitis at 16 weeks and led to a rapid reduction in pruritus from the first week. IGA 0/1 was reached in BREEZE-AD1 and BREEZE-AD2 at week 16, respectively, in 4.8% and 4.5% of patients in the placebo group and in 11.8% and 8.8% of the groups treated with baricitinib 1mg, 11.4% and 10.6% in those treated with baricitinib 2mg, and 16.8% and 13.8% of those treated with baricitinib 4mg.<a class="elsevierStyleCrossRef" href="#bib0825">58</a> The most common adverse events were nasopharyngitis, headache, and increased creatine phosphokinase. Long-term safety is currently being evaluated (NCT03334435<a class="elsevierStyleCrossRef" href="#bib0830">59</a>).Baricitinib was recently approved by the European Medicines Agency for treatment of moderate to severe atopic dermatitis in adult patients who were candidates for systemic treatment, with a recommended dose of 4mg/d.<a class="elsevierStyleCrossRef" href="#bib0685">30</a>Oral UpadacitinibUpadacitinib (Rinvoq, AbbVie) is a JAK1 inhibitor that has been approved for the treatment of rheumatoid arthritis.<a class="elsevierStyleCrossRef" href="#bib0835">60</a> The efficacy and safety profile of the drug in adults with moderate to severe atopic dermatitis was evaluated in a phase 2b clinical trial. A total of 167 patients were randomly assigned to receive 3 different doses of upadacitinib (7.5mg, 15mg, and 30mg daily) or placebo. The mean percentage improvement in the EASI at week 16 over baseline was higher than for placebo at all the doses of upadacitinib (39% for 7.5mg, 62% for 15mg, 74% for 30mg vs. 23% in the placebo group). An EASI100 response was observed in 24% of the patients treated with 30mg/d, but not in those treated with placebo.Results were recently published from 2 phase 3 trials, Measure Up 1 and Measure Up 2, which evaluate the efficacy and safety of upadacitinib for treatment of moderate to severe atopic dermatitis in adults and adolescents (NCT03569293<a class="elsevierStyleCrossRef" href="#bib0840">61</a> and NCT03607422<a class="elsevierStyleCrossRef" href="#bib0845">62</a>). EASI75 was achieved at 16 weeks by 70% and 60% of the patients who received upadacitinib 15mg (n=281 [Measure Up 1] and n=276 [Measure Up 2]), by 80% and 73% of those who received upadacitinib 30mg (n=285 [Measure Up 1] and n=282 [Measure Up 2]), and by only 16% and 13% in the placebo group (n=281 [Measure Up 1] and n=278 [Measure Up 2]). IGA 0/1 was achieved by 48% and 39% of patients treated with upadacitinib 15mg and 62% and 52% of those treated with upadacitinib 30mg, compared with 8% and 5% of the placebo groups. Both doses led to an early reduction in pruritus, which remained unchanged at 16 weeks. The most common adverse effects were acne, nasopharyngitis, upper respiratory tract infection, and headache.<a class="elsevierStyleCrossRefs" href="#bib0850">63,64</a>The safety and pharmacokinetics of various doses of upadacitinib are being evaluated in children with severe atopic dermatitis (NCT03646604<a class="elsevierStyleCrossRef" href="#bib0860">65</a>), and a phase 3 trial comparing upadacitinib with dupilimab in adults is currently underway (NCT03738397<a class="elsevierStyleCrossRef" href="#bib0865">66</a>).Oral AbrocitinibAbrocitinib may be effective and well-tolerated in patients with moderate to severe atopic dermatitis.A 12-week placebo-controlled phase 2b study included 269 adults treated with 4 daily doses of abrocitinib (10, 30, 100, and 200mg). The EASI improved significantly compared with placebo only for 100 and 200mg/d (reduction of 59% and 82.6% respectively vs. 35.2% in the placebo group), with a reduction in pruritus as early as day 2 of the study.<a class="elsevierStyleCrossRef" href="#bib0870">67</a>In a recent phase 3 trial, 391 adolescents and adults were treated with abrocitinib 200mg or 100mg or placebo over 12 weeks. A greater percentage of patients in the abrocitinib 200mg and 100mg groups vs. placebo reached IGA 0/1 (38.1% and 28.4% vs. 9.1%, respectively), EASI75 (61% and 44.5% vs. 10.4%, respectively), and EASI90 (37.7% and 23.9% vs. 3.9%, respectively). Adverse effects were recorded in 65.8% of patients who received 200mg, in 62.7% of the group that received 100mg, and in 53.8% of the placebo group. The most frequent were nausea in the 200-mg group, nasopharyngitis in the 100-mg group, and atopic dermatitis in the placebo group. Severe adverse effects were observed in the abrocitinib 200mg, 100mg, and placebo groups, affecting 1.3%, 3.2%, and 1.3% of patients, respectively. The effects considered to be associated with treatment included 1 case of herpangina and 1 case of pneumonia in the abrocitinib 100-mg group. Two patients in the abrocitinib 200-mg group developed herpes zoster, and 2 patients in the abrocitinib 100-mg group developed eczema herpeticum. Furthermore, in the group treated with 200mg, the platelet count decreased in 2 patients, and thrombocytopenia was detected in 5 patients.<a class="elsevierStyleCrossRef" href="#bib0875">68</a>The long-term safety and efficacy profile of abrocitinib is being studied in adolescents (NCT03796676,<a class="elsevierStyleCrossRef" href="#bib0880">69</a> NCT03627767,<a class="elsevierStyleCrossRef" href="#bib0885">70</a> NCT03422822,<a class="elsevierStyleCrossRef" href="#bib0890">71</a>). Ongoing studies are comparing the efficacy of oral abrocitinib with subcutaneous dupilumab in adults with atopic dermatitis (NCT04345367,<a class="elsevierStyleCrossRef" href="#bib0895">72</a> NCT03720470<a class="elsevierStyleCrossRef" href="#bib0900">73</a>).Oral GusacitinibGusacitinib (Asana BioSciences) is a dual inhibitor of the JAK and SYK pathways that is currently being trialed as oral medication. In a phase 1b trial involving 36 patients, EASI50 was achieved and pruritis decreased in almost all patients at 4 weeks of treatment with 20, 40, or 80mg. An EASI75 response was achieved in 63% of patients treated with 40mg and in 50% of those treated with 80mg/d compared with 22% in the placebo group. The improvement in the EASI response was associated with a decrease in the levels of the cutaneous biomarkers TH2 and TH22.<a class="elsevierStyleCrossRef" href="#bib0905">74</a>Results are pending from a phase 2b placebo-controlled trial to evaluate the efficacy and safety of ASN002 in 220 patients with moderate to severe atopic dermatitis (NCT03531957<a class="elsevierStyleCrossRef" href="#bib0910">75</a>).Topical RuxolitinibIn a phase 2b trial,<a class="elsevierStyleCrossRef" href="#bib0915">76</a> 307 patients with mild to moderate atopic dermatitis were randomized to receive ruxolitinib cream 1.5%/12h, 1.5%/24h, 0.5%/24h, or 0.15%/24h for 8 weeks, vehicle, or acetonide triamcinolone 0.1% cream every 12hours for 4 weeks. A therapeutic benefit was recorded for all of the ruxolitinib regimens at week 4, although the regimen that led to the greatest change in EASI was ruxolitinib 1.5%/12h (71.6% vs. 15.5% for vehicle). The improvement in EASI was greater in patients treated with ruxolitinib 1.5% every 12hours or every 24hours than in those treated with triamcinolone 0.1%, although the differences were not statistically significant. Furthermore, ruxolitinib managed to improve pruritis quickly. The improvement was maintained, the drug was well tolerated, and no relevant reactions were observed at the application site.A phase 1 trial is currently evaluating the safety and pharmacokinetics of topical ruxolitinib in pediatric patients (NCT03257644<a class="elsevierStyleCrossRef" href="#bib0920">77</a>), and other phase 3 trials include adolescents (NCT03745638,<a class="elsevierStyleCrossRef" href="#bib0925">78</a> NCT03745651<a class="elsevierStyleCrossRef" href="#bib0930">79</a>).Topical DelgocitinibThe JAK1, JAK2, and JAK3 inhibitor delgocitinib (Corectim, Japan Tobacco/LEO Pharma) was developed for topical treatment of atopic dermatitis.<a class="elsevierStyleCrossRef" href="#bib0935">80</a> Phase 1 and 2 studies<a class="elsevierStyleCrossRefs" href="#bib0940">81,82</a> proved the concept of therapeutic efficacy with respect to severity and pruritus. Pruritus improved 1 day after initiating delgocitinib, probably owing to the inhibition of IL-31.Results were recently published from a study that evaluated the safety and efficacy profile of delgocitinib 0.5% ointment in 158 Japanese patients aged ≥16 years with moderate to severe atopic dermatitis. The mean percentage change in EASI after 4 weeks was −44.3% in the delgocitinib group and 1.7% in the vehicle group; the results remained unchanged at 24 weeks. Various adverse effects were recorded, although these were mainly mild, affecting 4.7% of patients in the delgocitinib group and 1.9% in the vehicle group. The most common adverse effect was nasopharyngitis, followed by Kaposi varicelliform eruption and acne.<a class="elsevierStyleCrossRef" href="#bib0950">83</a>Topical delgocitinib 0.5% (Corectim) has been approved in Japan for treatment of atopic dermatitis.<a class="elsevierStyleCrossRef" href="#bib0955">84</a> Ongoing studies are evaluating various concentrations (NCT03725722<a class="elsevierStyleCrossRef" href="#bib0960">85</a>) and include pediatric patients (NCT03826901<a class="elsevierStyleCrossRef" href="#bib0965">86</a>).Other OptionsAn ongoing study is evaluating the safety and efficacy profile of the JAK1 inhibitor SHR0302 (NCT04162899<a class="elsevierStyleCrossRef" href="#bib0970">87</a>) for treatment of patients with moderate to severe atopic dermatitis. Results are pending from another study with topical brepocitinib for treatment of mild to moderate atopic dermatitis (NCT03903822).<a class="elsevierStyleCrossRef" href="#bib0975">88</a>Other Applications in DermatologyJAK inhibitors were recently used for the treatment of other treatment-refractory dermatologic conditions in which activation of the JAK/STAT pathway plays a key role (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>ConclusionsDysregulation of the JAK/STAT pathway could intervene in the pathogenesis of many dermatologic diseases, including vitiligo, alopecia areata, psoriasis, and atopic dermatitis. JAK inhibitors, which have an acceptable safety profile, could be used for the simultaneous treatment of pathogenically similar inflammatory skin diseases with common signaling pathways.In the case of moderate to severe psoriasis, tofacitinib has been evaluated in phase 1, 2, and 3 trials, all of which show it to be efficacious, especially at 10mg/12h, although the drug has not been approved by regulatory committees. Recent data suggest that TYK2 inhibitors could show promising results for the treatment of psoriasis. One such drug, deucravacitinib, has shown maximum efficacy for oral treatment of psoriasis. Current therapeutic options in atopic dermatitis are limited, although oral and topical JAK inhibitors have yielded promising results, with improvement in the severity of atopic dermatitis and a rapid and marked improvement in pruritus and quality of life. Baricitinib was recently approved for the treatment of moderate to severe atopic dermatitis in adults.In the future, JAK inhibitors could prove to be a real alternative therapy for some inflammatory skin diseases. Selective inhibitors have a superior safety and efficacy profile, whereas nonselective inhibitors are being developed mainly for topical use. The inhibition of multiple signals, especially the response to interferon, could increase susceptibility to infection and viral reactivation. While the safety and efficacy profile seems favorable for the moment, more studies are necessary to determine the doses that will optimize efficacy, cost-effectiveness, and safety of this drug family for potential use in skin conditions in the long term.Conflicts of InterestC. Garcia-Melendo declares that she has no conflicts of interest.X. Cubiró has received fees from Novartis, Leo-Pharma, and Almirall.L. Puig has received fees and/or has participated in clinical trials sponsored by AbbVie, Almirall, Amgen, Baxalta, Biogen, Boehringer Ingelheim, Celgene, Gebro, Janssen, JS BIOCAD, Leo-Pharma, Lilly, Merck-Serono, MSD, Mylan, Novartis, Pfizer, Regeneron, Roche, Sandoz, Samsung-Bioepis, Sanofi, and UCB." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres1542263" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1395149" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1542262" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1395148" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Psoriasis" "secciones" => array:9 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Oral Tofacitinib" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Topical Tofacitinib" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Topical Ruxolitinib" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Oral Baricitinib" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Oral Abrocitinib" ] 5 => array:2 [ "identificador" => "sec0040" "titulo" => "Oral Solcitinib" ] 6 => array:2 [ "identificador" => "sec0045" "titulo" => "Oral Itacitinib Adipate" ] 7 => array:2 [ "identificador" => "sec0050" "titulo" => "Oral Peficitinib" ] 8 => array:2 [ "identificador" => "sec0055" "titulo" => "TYK2 Inhibitors" ] ] ] 6 => array:3 [ "identificador" => "sec0060" "titulo" => "Atopic Dermatitis" "secciones" => array:9 [ 0 => array:2 [ "identificador" => "sec0065" "titulo" => "Oral Tofacitinib" ] 1 => array:2 [ "identificador" => "sec0070" "titulo" => "Topical Tofacitinib" ] 2 => array:2 [ "identificador" => "sec0075" "titulo" => "Oral Baricitinib" ] 3 => array:2 [ "identificador" => "sec0080" "titulo" => "Oral Upadacitinib" ] 4 => array:2 [ "identificador" => "sec0085" "titulo" => "Oral Abrocitinib" ] 5 => array:2 [ "identificador" => "sec0090" "titulo" => "Oral Gusacitinib" ] 6 => array:2 [ "identificador" => "sec0095" "titulo" => "Topical Ruxolitinib" ] 7 => array:2 [ "identificador" => "sec0100" "titulo" => "Topical Delgocitinib" ] 8 => array:2 [ "identificador" => "sec0105" "titulo" => "Other Options" ] ] ] 7 => array:2 [ "identificador" => "sec0110" "titulo" => "Other Applications in Dermatology" ] 8 => array:2 [ "identificador" => "sec0115" "titulo" => "Conclusions" ] 9 => array:2 [ "identificador" => "sec0120" "titulo" => "Conflicts of Interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2020-09-30" "fechaAceptado" => "2020-12-21" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1395149" "palabras" => array:4 [ 0 => "JAK/STAT pathway" 1 => "Janus kinase inhibitors" 2 => "Psoriasis" 3 => "Atopic dermatitis" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1395148" "palabras" => array:4 [ 0 => "JAK/STAT" 1 => "Inhibidores de JAK" 2 => "Psoriasis" 3 => "Dermatitis atópica" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Dermatologists’ interest in the Janus-associated kinase (JAK)/signal transducers and activators of transcription (STAT) pathway has been growing as evidence builds to support its key role in the pathogenesis of inflammatory skin diseases. Because certain proinflammatory cytokines use the JAK/STAT pathway for signal transduction, it has become a promising therapeutic target in diseases where selective modulation of the immune system can be useful. We aim to review current knowledge of the JAK/STAT signaling pathway and its role in immune-mediated skin diseases. In the second part of the review we cover the efficacy and safety of oral and topical JAK inhibitors in the treatment of psoriasis, atopic dermatitis, and other skin diseases." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La vía de señalización de citocinas Janus cinasa/transductor de señal y activador de transcripción (JAK/STAT) es un área de interés emergente en dermatología, con evidencia creciente del papel clave en la patogénesis de las enfermedades inflamatorias cutáneas. Debido a que algunas citocinas proinflamatorias usan la vía JAK/STAT para la transducción de señales se convierte en una diana terapéutica prometedora para el tratamiento de dichas enfermedades al modular de forma selectiva el sistema inmune. El objetivo de esta revisión es conocer la vía de señalización JAK/STAT y su papel en distintas enfermedades dermatológicas inmunomediadas. En esta segunda parte, se revisará la eficacia y seguridad de los inhibidores de JAK –en formulación oral o tópica– para el tratamiento de la psoriasis, la dermatitis atópica y otras dermatosis." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Garcia-Melendo C, Cubiró X, Puig L. Inhibidores de JAK: usos en dermatología. Parte 2: aplicaciones en psoriasis, dermatitis atópica y otras dermatosis. Actas Dermosifiliogr. 2021;112:586–600." ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1650 "Ancho" => 2917 "Tamanyo" => 276752 ] ] "descripcion" => array:1 [ "en" => "IL-4/IL-13/JAK/STAT signaling pathway and SYK pathway in atopic dermatitis. The figure shows various JAK inhibitors and dual JAK/SYK inhibitors in atopic dermatitis. The biological functions of IL-4 and IL-13 are mediated by their binding to the subunits IL-4Rα and IL-13Rα1 of the corresponding receptors. IL-4 binds to a type 1 receptor that includes IL-4Rα and the γ chain of the cytokine receptor or a type 2 receptor configured by IL-4Rα and IL-13R α1. The latter is the main IL-13 receptor. IL-5 produced as a result of polarization of type 2 helper T cells binds to the IL-5Rα subunit of its receptor to form a complex with a shared signaling subunit, the β chain, and induce phosphorylation of JAK1/JAK2 and activation of STAT1, STAT3, and STAT5. Via its SH2 domains, SYK binds to diphosphorylated immunoreceptor tyrosine-based activation motifs (ITAM) in the cytoplasm of various immune receptors, such as T-, B-, NK-cell receptors or the various receptors for the constant fraction of immunoglobulin (Fc) in neutrophils, mastocytes, macrophages dendritic cells, and other strains of the immune system. This interaction results in the activation of other proteins that transmit downstream signals. Figure generated with the assistance of Biorender.com." ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "Ongoing trials: information from ClinicalTrials.gov.<a class="elsevierStyleCrossRef" href="#bib1070">107</a>Abbreviations. CDASI, Cutaneous Dermatomyositis Disease Area and Severity Index; CK, creatine kinase; CLASI, Cutaneous Lupus Erythematosus Disease Area and Severity Index; CMV, cytomegalovirus; CSAMI, cutaneous sarcoidosis activity and morphology instrument; DM, dermatomyositis; GVHD, graft-versus-host disease; HCQ, hydroxychloroquine; HS, hidradenitis suppurativa; SLE, systemic lupus erythematosus; LPPAI, Lichen Planopilaris Activity Index; MMF, mycophenolate mofetil; MTX, methotrexate; PDN, prednisone; PG, pyoderma gangrenosum; SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index-2000." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Disease \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">JAK Inhibitor \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Study \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Outcome \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Safety \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowgroup " rowspan="6" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dermatomyositis</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowgroup " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Oral tofacitinib</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Kurtzman et al. (2016)<a class="elsevierStyleCrossRef" href="#bib0980">89</a>- n=3 (2 with classic DM and 1 with amyopathic DM)- Tofacitinib 5–10mg/12h (1 patient received concomitant hydroxychloroquine) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- Clinical response at 4 wk- Mean treatment period, 9.6 mo- Mean improvement in CDASI score, 12 points- Pruritus improved in all patients- Strength and fatigue improved in all patients with classic DM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No adverse effects reported \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Wendel et al. (2019)<a class="elsevierStyleCrossRef" href="#bib0985">90</a>- n=2- Patient A: Classic DM with muscular and subcutaneous calcifications. Treated with tofacitinib 5mg/12h+MTX 12.5mg/wk+PDN 5mg/d- Patient B: Classic DM with calcifications and interstitial lung disease. CDASI 25. Treated with tofacitinib 5mg/12h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- Patient A: Stabilization of calcifications at 2 wk. Calcifications stable or regressing at week 28, with no acral ulcers- Patient B: Improvement in respiratory, cutaneous, and musculoskeletal symptoms. CDASI 10 at 12 wk. CDASI 3 at 28 wk, with no new calcifications and improvement or stabilization of previous calcifications \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- Patient A: Transient and moderate hypercalcinemia, weight gain- Patient B: Weight gain \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NCT03002649<a class="elsevierStyleCrossRef" href="#bib0990">91</a>- Phase 11- n=10- Patients with refractory DM- Tofacitinib 11mg/24h, 12 wk of treatment with an extension of 4 wk \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No results available \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No results available \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowgroup " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Oral ruxolitinib</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hornung et al. (2014)<a class="elsevierStyleCrossRef" href="#bib0995">92</a>- n=1- Classic DM, CDASI=30- Ruxolitinib 15mg/12h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- CDASI=0 at 2 mo -Recovery of muscle strength \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No adverse effects reported \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fetter et al. (2020)<a class="elsevierStyleCrossRef" href="#bib1000">93</a>- n=1- Six-year history of classic DM +10-year history of alopecia areata- Ruxolitinib 10mg/12h→30mg/24h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- Improvement in muscle pain, muscle strength, and skin lesions of DM at 4 mo. Regrowth of hair and eyebrows \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No adverse effects reported \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Jalles et al. (2020)<a class="elsevierStyleCrossRef" href="#bib1005">94</a>- n=1- Classic DM, with MDA5+and rapidly progressive interstitial pneumonia- Ruxolitinib 15mg/12h+corticosteroids 4mg/24h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- Stabilization of symptoms at 9 mo, with no signs of disease activity affecting the muscles, lungs, or skin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Development of small cell lung carcinoma. Discontinuation of ruxolitinib \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_colgroup " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowgroup " rowspan="7" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cutaneous GVHD</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowgroup " rowspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Oral ruxolitinib</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Spoerl et al. (2014)<a class="elsevierStyleCrossRef" href="#bib1010">95</a>- n=4- Patients with cutaneous GVHD refractory to 2 previous immunosuppressants and corticosteroids. Area affected 50%- Oral ruxolitinib 10mg/12h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- Reduction of the affected area to<25%- Response in 1 wk and 1.5 wk \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No adverse effects reported \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Zeiser et al. (2015)<a class="elsevierStyleCrossRef" href="#bib1015">96</a>- Retrospective study of 19 centers in Europe and the USA.- 95 patients with corticosteroid-refractory GVHD (acute GVHD n=54, chronic GVHD n=41), all moderate to severe.- Ruxolitinib 5–10mg/12h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- Acute GVHD: the global response rate was 81.5% (44/54), including 25 complete responses (46.3%). Median time to response, 1.5 wk.- Chronic GVHD: overall response rate, 85.4% (35/41); partial response 78% (32/41); and complete response, 7.3% (3/41). Median time to response, 3 wk.- Very satisfactory response in patients with skin involvement. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cytopenia (55.6% in the acute GVHD group and 17.1% in the chronic GVHD group)Reactivation of CMV (33.3% in acute GVHD and 14.6% chronic GVHD) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sarmiento et al. (2017)<a class="elsevierStyleCrossRef" href="#bib1020">97</a>- n=8- GVHD refractory to corticosteroids and extracorporeal photopheresis. Acute GVHD, 3 patients (1 pulmonary, 2 cutaneous, 1 multisystemic); chronic GVHD, 5 patients (3 cutaneous)- Oral ruxolitinib, 10–20mg/d \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Response in 85% and complete response in 50% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 patients required dose reduction owing to grade 2 neutropenia \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ongoing trials:- Phase 2: NCT03491215NCT02953678NCT03616184- Phase 3:NCT02913261NCT03112603 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No results available \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No results available \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Oral itacitinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ongoing trialsPhase 1: NCT03497273Phase 2: NCT03846479Phase 3: NCT03584516 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No results available \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No results available \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Topical ruxolitinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ongoing trialsPhase 2 NCT03395340 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No results available \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No results available \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Oral baricitinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ongoing trialsPhase 1/2: NCT02759731 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No results available \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No results available \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_colgroup " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hidradenitis suppurativa</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Oral tofacitinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Savage et al. (2020)<a class="elsevierStyleCrossRef" href="#bib1025">98</a>- n=2- Patient A: Hurley stage III HS. Treated with tofacitinib 5mg/12h+amoxicillin 500mg/12h+ciclosporin 5mg/kg- Patient B: Hurley stage III HS. Tofacitinib 5mg/12h+amoxicillin-clavulanate 3 wk+azithromycin 1 wk+MMF 1250mg/12h+topical corticosteroids \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- Patient A: Reduced pain and number of lesions at 4 mo, enabling dose of ciclosporin to be reduced. No pain at 11 mo, with persistence only of inactive lesions- Patient B: Reduction in number of admissions, improvement in ulcers \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- Patient A. No adverse effects- Patient B: Herpes zoster 3 y after initiation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Oral INCB054707 (JAK1 inhibitor) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ongoing trialsPhase 2:NCT03607487NCT03569371 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No results available \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No results available \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_colgroup " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowgroup " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lichen planus</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Oral tofacitinib</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Yang et al. (2018)<a class="elsevierStyleCrossRef" href="#bib1030">99</a>- Lichen planopilaris n=10- Tofacitinib 10–15mg/d for 2–19 mo- Adjuvant treatment: intralesional triamcinolone (2 patients), HCQ (1 patient), intralesional triamcinolone +HCQ (1 patient), intralesional triamcinolone+tacrolimus ointment (1 patient) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- Clinical response in 8 patients (4 in monotherapy and 4 with adjuvant therapy)- LPPAI 6.22 at baseline and 3.08 after treatment. Reduction in LPPAI score of 30%-94%. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Weight gain in 1 patient (4.5kg at 12 mo) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Damsky et al. (2020)<a class="elsevierStyleCrossRef" href="#bib1035">100</a>- n=3 with erosive lichen planus refractory to previous treatments (patient 1: prednisone, methylprednisolone; patient 2: methotrexate, mycophenolate mofetil, ciclosporin; patient 3: prednisone, acitretin).- Tofacitinib 5mg/12h- Patient 1 received adjuvant therapy with MTX and PDN 10mg daily \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- Patient A: Remission of symptoms and lesions Recurrence on suspending tofacitinib and MTX, improvement when tofacitinib was reintroduced- Patient B: Resolution of pain and bleeding. Remission of lesions.- Patient C: Resolution of pain. Remission of lesions. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No adverse effects reported \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Topical ruxolitinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ongoing trialsPhase 2 NCT03697460 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No results available \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No results available \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_colgroup " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowgroup " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cutaneous lupus erythematosus</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Oral ruxolitinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Wenzel et al. (2016)<a class="elsevierStyleCrossRef" href="#bib1040">101</a>- n=1Patient with primary myelofibrosis and chilblain lupus-Ruxolitinib 20mg/12h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Complete remission of skin lesions at 4 mo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No adverse effects reported \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Baricitinib oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Wallace et al. (2018)<a class="elsevierStyleCrossRef" href="#bib1045">102</a>- Phase 2 trial, 24 wk- n=314, randomized to placebo, baricitinib 2mg/d, or baricitinib 4mg/d (1:1:1)- Patients with SLE. Mucocutaneous activity measured by SLEDAI-2K in 84%, although CLASI low \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No significant improvement observed in skin lesions.Baseline CLASI 4.2, which is probably not sufficient to reveal differences between the placebo and treatment groups. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Severe infection in 6% of the baricitinib 4mg group, 2% of the 2mg group, and 1% of the placebo group.Baricitinib led to dose-dependent reductions in hemoglobin, neutrophil, and triglyceride values and increase in platelet, CK, HDL cholesterol, and total cholesterol values \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Oral tofacitinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ongoing trialsPhase 1: NCT03159936 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No results available \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No results available \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_colgroup " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Chronic hand eczema \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Topical delgocitinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ongoing trialsPhase 2:NCT03683719NCT02664805 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No results available \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No results available \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_colgroup " colspan="5" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowgroup " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pyoderma gangrenosum</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Oral tofacitinib</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gregory et al. (2019)<a class="elsevierStyleCrossRef" href="#bib1050">103</a>- n=1.- Oral tofacitinib 10mg/12h+infliximab 10mg/kg (every 4wk) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lesion almost completely healed 3 wk after adding tofacitinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No adverse effects reported \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Kochar et al. (2019)<a class="elsevierStyleCrossRef" href="#bib1055">104</a>- n=3. Crohn disease and refractory PG- Treated with tofacitinib 5–10mg/12h for severe inflammatory arthritis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">- Patient A: Improvement at 2 wk, resolution of PG at 12 wk- Patient B: PG completely healed at 12 wk- Patient C: Lesions improved at 1 mo, although the dose had to be increased to 10mg/12h for complete resolution \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No adverse effects reported \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Oral ruxolitinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Nasifoglu et al. (2018)<a class="elsevierStyleCrossRef" href="#bib1060">105</a>- n=1- Concomitant polycythemia vera with mutated JAK2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Rapid improvement in PG and disappearance of lesion at 4 y \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No adverse effects reported \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cutaneous sarcoidosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Oral tofacitinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Damsky et al. (2019)<a class="elsevierStyleCrossRef" href="#bib1065">106</a>- n=3- Tofacitinib 5mg/12h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Complete response in 2 patientsOne patient lost to follow-up after a 96% in CSAMI at 4 mo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No adverse effects reported \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Granuloma annulare \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Oral tofacitinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Damsky et al. (2019)<a class="elsevierStyleCrossRef" href="#bib1065">106</a>- n=1- Tofacitinib 5mg/12h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Complete response \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No adverse effects reported \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2648062.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "The table shows the studies performed or underway with JAK inhibitors for the treatment of various skin conditions, the main results obtained, and the safety of the drugs. Available evidence for JAK inhibitors is based mainly on case series, although clinical trials are ongoing." ] ] ] "descripcion" => array:1 [ "en" => "Use of JAK Inhibitors in Other Skin Conditions<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:107 [ 0 => array:3 [ "identificador" => "bib0540" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "JAK inhibitors in dermatology: the promise of a new drug class" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "W. 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Janus Kinase Inhibitors in Dermatology: Part 2: Applications in Psoriasis, Atopic Dermatitis, and Other Dermatoses

Inhibidores de JAK: usos en dermatología. Parte 2: aplicaciones en psoriasis, dermatitis atópica y otras dermatosis

C. Garcia-Melendo

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cris.garciamelendo@gmail.com

Corresponding author.

, X. Cubiró, L. Puig

Servicio de Dermatología, Hospital de la Santa Creu i Sant Pau, Barcelona, Universitat Autònoma de Barcelona, Barcelona, Spain

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    "titulo" => "Janus Kinase Inhibitors in Dermatology&#58; Part 2&#58; Applications in Psoriasis&#44; Atopic Dermatitis&#44; and Other Dermatoses"
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            "entidad" => "Servicio de Dermatolog&#237;a&#44; Hospital de la Santa Creu i Sant Pau&#44; Barcelona&#44; Universitat Aut&#242;noma de Barcelona&#44; Barcelona&#44; Spain"
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        "titulo" => "Inhibidores de JAK&#58; usos en dermatolog&#237;a&#46; Parte 2&#58; aplicaciones en psoriasis&#44; dermatitis at&#243;pica y otras dermatosis"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">IL-4&#47;IL-13&#47;JAK&#47;STAT signaling pathway and SYK pathway in atopic dermatitis&#46;</p> <p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The figure shows various JAK inhibitors and dual JAK&#47;SYK inhibitors in atopic dermatitis&#46; The biological functions of IL-4 and IL-13 are mediated by their binding to the subunits IL-4R&#945; and IL-13R&#945;1 of the corresponding receptors&#46; IL-4 binds to a type 1 receptor that includes IL-4R&#945; and the &#947; chain of the cytokine receptor or a type 2 receptor configured by IL-4R&#945; and IL-13R &#945;1&#46; The latter is the main IL-13 receptor&#46;</p> <p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">IL-5 produced as a result of polarization of type 2 helper T cells binds to the IL-5R&#945; subunit of its receptor to form a complex with a shared signaling subunit&#44; the &#946; chain&#44; and induce phosphorylation of JAK1&#47;JAK2 and activation of STAT1&#44; STAT3&#44; and STAT5&#46;</p> <p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Via its SH2 domains&#44; SYK binds to diphosphorylated immunoreceptor tyrosine-based activation motifs &#40;ITAM&#41; in the cytoplasm of various immune receptors&#44; such as T-&#44; B-&#44; NK-cell receptors or the various receptors for the constant fraction of immunoglobulin &#40;Fc&#41; in neutrophils&#44; mastocytes&#44; macrophages dendritic cells&#44; and other strains of the immune system&#46; This interaction results in the activation of other proteins that transmit downstream signals&#46;</p> <p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Figure generated with the assistance of Biorender&#46;com&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Part 1 of this review provided a detailed description of the Janus kinase&#47;signal transducer and activator of transcription &#40;JAK&#47;STAT&#41; intracellular signaling pathway&#46; The potential role of JAK inhibitors in the treatment of various dermatologic diseases was highlighted&#44; with emphasis on available evidence for vitiligo and alopecia areata&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Here&#44; in Part 2&#44; we review pathogenesis and the role of the JAK&#47;STAT pathway in psoriasis and atopic dermatitis&#44; as well as in other skin conditions such as hidradenitis&#44; dermatomyositis&#44; and graft-versus-host disease&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Psoriasis</span><p id="par0015" class="elsevierStylePara elsevierViewall">The interleukin &#40;IL&#41; 23&#47;IL-17 &#40;IL-23&#47;IL-17&#41; axis is currently considered the main pathogenic pathway in psoriasis&#46; However&#44; several cytokines play a role in this disease&#44; and some transmit their signal after binding to the corresponding receptors via the JAK&#47;STAT pathway&#46; These include interferon &#40;IFN&#41; &#947;&#44; IFN-&#945;&#44; IL-2&#44; IL-6&#44; IL-12&#44; IL-13&#44; IL-19&#44; IL-20&#44; IL-21&#44; IL-22&#44; and IL-23&#46; Tumor necrosis factor &#40;TNF&#41; &#945; and other cytokines&#44; such as IL-17&#44; IL-8&#44; and those of the IL-1 family &#40;IL-1&#44; IL-18&#44; IL-36&#44; and IL-38&#41;&#44; do not directly activate the JAK&#47;STAT pathway&#44; although their activity can be suppressed indirectly through inhibition of the JAK&#47;STAT pathway&#46;<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">1&#8211;3</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">JAK signaling has been shown to be overregulated&#44; with increased expression of STAT1 and STAT3 in lesional psoriatic skin when compared with healthy skin&#46;<a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">4&#8211;6</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">STAT1 is responsible for the transduction of type 1 IFN signals &#40;&#945; and &#946;&#41; and type 2 signals &#40;&#947;&#41; via a JAK1&#47;JAK2&#8211;dependent mechanism&#44; leading to production of multiple proinflammatory mediators and activation and maturation of dendritic cells with stimulation of type 1 helper T cells &#40;T<span class="elsevierStyleInf">H</span>1&#41; and T<span class="elsevierStyleInf">H</span>17&#46;<a class="elsevierStyleCrossRefs" href="#bib0570"><span class="elsevierStyleSup">7&#44;8</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">STAT3 is involved in the induction and differentiation of T<span class="elsevierStyleInf">H</span>17 cells via activation of JAK2&#47;TYK2 induced by IL-23&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">9</span></a> In addition&#44; T<span class="elsevierStyleInf">H</span>17 cells can produce IL-22&#44; which is responsible for epidermal hyperplasia and production of antimicrobial peptides by keratinocytes&#46;<a class="elsevierStyleCrossRefs" href="#bib0545"><span class="elsevierStyleSup">2&#44;10</span></a> STAT3 also participates in the proliferation of keratinocytes via IL-6&#8211;induced activation of JAK1&#47;JAK2 or JAK1&#47;TYK2<a class="elsevierStyleCrossRefs" href="#bib0590"><span class="elsevierStyleSup">11&#44;12</span></a> and is indirectly activated by IL-17 through induction of IL-19 and&#47;or IL-36 by keratinocytes&#46;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">13</span></a></p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Oral Tofacitinib</span><p id="par0035" class="elsevierStylePara elsevierViewall">Tofacitinib &#40;Xeljanz&#44; Pfizer&#41; mainly inhibits JAK1 and JAK3&#46; It has been approved by the United States Food and Drug Administration &#40;FDA&#41; for the treatment of adults with psoriatic arthritis and for the treatment of moderate to severe rheumatoid arthritis at doses of 5<span class="elsevierStyleHsp" style=""></span>mg twice daily&#46;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">14</span></a> It was recently approved for the treatment of polyarticular juvenile idiopathic arthritis in children aged &#8805;2 years&#44;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">15</span></a> as well as for treatment of ulcerative colitis at doses of 10<span class="elsevierStyleHsp" style=""></span>mg twice daily for 8 weeks and subsequently at 5<span class="elsevierStyleHsp" style=""></span>mg twice daily&#46;<a class="elsevierStyleCrossRefs" href="#bib0605"><span class="elsevierStyleSup">14&#44;16</span></a> Tofacitinib has proven effective in moderate to severe psoriasis in phase 2 and 3 trials&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">In a study of 197 patients&#44; treatment with tofacitinib 2<span class="elsevierStyleHsp" style=""></span>mg&#44; 5<span class="elsevierStyleHsp" style=""></span>mg&#44; and 15<span class="elsevierStyleHsp" style=""></span>mg twice daily achieved a Psoriasis Area and Severity Index 75 &#40;PASI75&#41; response rate of 25&#37;&#44; 41&#37;&#44; and 67&#37;&#44; respectively&#44; at 12 weeks&#44; compared with 2&#37; for placebo&#46; PASI90 was achieved at 12 weeks by 22&#37; of those who received tofacitinib&#46;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">17</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">A phase 3 trial of 1106 patients with plaque psoriasis and PASI &#8805;12 revealed the noninferiority of tofacitinib 10<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h to subcutaneous etanercept 50<span class="elsevierStyleHsp" style=""></span>mg at week 12&#44; with a similar rate of adverse events in each group&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">18</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Two phase 3 trials &#40;OPT Pivotal 1 &#91;901 patients&#93; and OPT Pivotal 2 &#91;960 patients&#93;<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">19</span></a>&#41;&#44; tofacitinib 10<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h was more efficacious than 5<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h from week 16 onward&#44; with a greater PASI75 response rate between week 16 and week 28&#46; Among the patients who reached PASI75 at week 16&#44; the response was maintained at 52 weeks in 74&#46;1&#37; of the 5<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h group and 79&#46;4&#37; of the 10<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h group&#44; and most continued to do so at 24 months&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">20</span></a> In addition&#44; at 16 weeks of treatment&#44; both doses led to an improvement in ungual psoriasis&#44; pruritus &#40;the difference was evident 1 day after initiation of treatment&#41;&#44; and the Dermatology Life Quality Index&#46; The improvement was maintained at week 52&#46;<a class="elsevierStyleCrossRefs" href="#bib0640"><span class="elsevierStyleSup">21&#44;22</span></a> Another phase 3 trial achieved an American College of Rheumatology &#40;ACR&#41; 20 response at week 16 in all patients with psoriatic arthritis treated with tofacitinib &#40;5<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h or 10<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&#41; and an ACR50 or ACR70 in more than half&#46; The responses were maintained at week 52&#46;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">23</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Most adverse effects were mild or moderate&#46; In the tofacitinib groups&#44; 12 patients had herpes zoster&#44; although the most frequent adverse effect was nasopharyngitis&#46;<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">19</span></a> Two patients treated with tofacitinib 10<span class="elsevierStyleHsp" style=""></span>mg every 12<span class="elsevierStyleHsp" style=""></span>h in OPT Pivotal 1 had severe infections &#40;appendicitis&#44; pneumonia&#44; and pyelonephritis&#41;&#44; whereas 3 patients who received tofacitinib 5<span class="elsevierStyleHsp" style=""></span>mg every 12<span class="elsevierStyleHsp" style=""></span>h in OPT Pivotal 2 had severe infections &#40;pneumonia&#44; herpes zoster&#44; erysipelas&#41;&#46; Both studies reported an increase in cholesterol and creatine phosphokinase and reduced hemoglobin&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">The adverse effects of tofacitinib are similar at 5<span class="elsevierStyleHsp" style=""></span>mg and 10<span class="elsevierStyleHsp" style=""></span>mg&#44; with the most frequent being mild cytopenia&#44; upper respiratory tract infections&#44; headache&#44; urinary tract infection&#44; and diarrhea&#46;<a class="elsevierStyleCrossRefs" href="#bib0620"><span class="elsevierStyleSup">17&#44;19&#44;20&#44;24</span></a> In October 2015&#44; the FDA refused to approve tofacitinib for treatment of moderate to severe plaque psoriasis&#44; alleging that more studies were necessary on long-term safety&#46;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">25</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Topical Tofacitinib</span><p id="par0065" class="elsevierStylePara elsevierViewall">Topical tofacitinib could be an alternative therapy in mild to moderate plaque psoriasis&#46; It has a favorable safety profile&#44; although the improvement reported in published studies is slight&#46; In a phase 2a study of 71 patients&#44; the authors reported promising results with tofacitinib ointment 2&#37; every 12<span class="elsevierStyleHsp" style=""></span>hours&#46; The percentage change in the Target Plaque Severity Score at week 4 with respect to baseline was statistically significant with tofacitinib ointment compared with the vehicle &#40;minimum mean square&#44; &#8722;54&#46;4&#37; vs&#46; &#8722;41&#46;5&#37;&#44; respectively&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">26</span></a> A subsequent multicenter randomized study including 435 patients who received tofacitinib ointment 1&#37; and 2&#37; revealed greater efficacy than the vehicle for treatment of psoriasis at week 8 &#40;Physician&#39;s Global Assessment &#91;PGA&#93; 0&#47;1 in 18&#46;6&#37; of patients for tofacitinib 2&#37; every 24<span class="elsevierStyleHsp" style=""></span>hours and 22&#46;5&#37; for tofacitinib 2&#37; every 12<span class="elsevierStyleHsp" style=""></span>hours&#41;&#44; although not at week 12&#46; Reactions were observed at the application site in 8&#46;1&#37; of patients&#44; although the highest incidence recorded for patients who received vehicle&#46;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">27</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Topical Ruxolitinib</span><p id="par0070" class="elsevierStylePara elsevierViewall">The JAK1&#47;2 inhibitor ruxolitinib has been assessed as topical treatment for psoriasis&#46; In a phase 2 clinical trial&#44; 29 patients were randomized to receive ruxolitinib cream 0&#46;5&#37; or 1&#37; once daily or 1&#46;5&#37; twice daily for 28 days&#44; vehicle&#44; or an active comparator &#40;calcipotriene cream 0&#46;005&#37; or betamethasone dipropionate 0&#46;05&#37;&#41;&#46; Treatment with ruxolitinib cream 1&#37; and 1&#46;5&#37; was safe&#44; well tolerated&#44; and effective&#44; with reduced plaque thickness&#44; erythema&#44; scaling&#44; and lesion size compared with the vehicle &#40;reduction of 53&#37; in the treatment groups vs&#46; 32&#37; in the vehicle group&#41;&#46; No significant differences in efficacy were found between ruxolitinib and the active comparators&#46;<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">28</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Oral Baricitinib</span><p id="par0075" class="elsevierStylePara elsevierViewall">Baricitinib &#40;Olumiant&#44; Lilly&#41; is a JAK1&#47;2 inhibitor that has been approved by the FDA<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">29</span></a> and the European Medicines Agency &#40;EMA&#41;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">30</span></a> for the treatment of moderate to severe rheumatoid arthritis at recommended doses of 4<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#46; It was recently approved for the treatment of moderate to severe atopic dermatitis&#46;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">30</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Baricitinib was studied in a phase 2b trial for treatment of moderate to severe plaque psoriasis in 271 patients&#46; The PASI75 at week 12 was significantly higher for the groups treated with 8<span class="elsevierStyleHsp" style=""></span>mg and 10<span class="elsevierStyleHsp" style=""></span>mg once daily than for placebo &#40;42&#46;9&#37;&#44; 54&#46;1&#37;&#44; and 16&#46;1&#37;&#44; respectively&#41;&#46; The most common adverse effects were infection&#44; with an incidence rate of 26&#46;5&#37; in the placebo group and 21&#46;5&#37; in the baricitinib groups&#44; the most common being nasopharyngitis&#46;<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">31</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Oral Abrocitinib</span><p id="par0085" class="elsevierStylePara elsevierViewall">Abrocitinib &#40;Pfizer&#41; is a JAK1 inhibitor that was assessed for the treatment of moderate to severe psoriasis in a phase 2 trial lasting 12 weeks&#44; in which 59 patients were randomly assigned to receive 200<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h&#44; 400<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h&#44; 200<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&#44; or placebo for 4 weeks&#46; At week 4&#44; the percentage of patients who achieved PASI75 was 17&#37; for the placebo and 200<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h groups&#44; 50&#37; for the 400<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h group&#44; and 60&#37; for the 200<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h group&#46; More laboratory abnormalities &#40;low neutrophil&#44; platelet&#44; and reticulocyte counts&#41; were observed in the 200<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h group&#44; although no associated bleeding or severe infections were recorded&#46;<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">32</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Oral Solcitinib</span><p id="par0090" class="elsevierStylePara elsevierViewall">A dose-dependent improvement in psoriasis was recorded with solcitinib &#40;GlaxoSmithKline&#41;&#44; a JAK1 inhibitor that was assessed in a phase 2 trial&#46; The study population comprised 60 patients&#44; of whom 13&#37; achieved PASI75 at 100<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#44; 25&#37; at 200<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#44; 57&#37; at 400<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#44; and 0&#37; with placebo&#46;<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">33</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Oral Itacitinib Adipate</span><p id="par0095" class="elsevierStylePara elsevierViewall">The JAK1 inhibitor itacitinib adipate &#40;Incyte Corporation&#41; led to a significant improvement in patients with moderate to severe psoriasis in a phase 2 trial including 50 patients and lasting 12 weeks&#46; At 1 month&#44; PASI75 was achieved by 0&#37;&#44; 11&#46;1&#37;&#44; 0&#37;&#44; 22&#46;2&#37;&#44; and 27&#46;7&#37; in the placebo&#44; 100<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h&#44; 200<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h&#44; 200<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&#44; and 600<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h groups&#44; respectively&#46; The only significant differences with placebo were observed in the itacitinib 600<span class="elsevierStyleHsp" style=""></span>mg&#47;d group&#46;<a class="elsevierStyleCrossRef" href="#bib0705"><span class="elsevierStyleSup">34</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Oral Peficitinib</span><p id="par0100" class="elsevierStylePara elsevierViewall">Peficitinib &#40;Smyraf&#44; Astellas Pharma Inc&#46;&#41; is a pan-JAK inhibitor that has been approved in Japan for treatment of rheumatoid arthritis<a class="elsevierStyleCrossRef" href="#bib0710"><span class="elsevierStyleSup">35</span></a> that proved efficacious in a phase 2 trial including 124 patients with moderate to severe plaque psoriasis&#46; Patients received active treatment &#40;10<span class="elsevierStyleHsp" style=""></span>mg&#44; 25<span class="elsevierStyleHsp" style=""></span>mg&#44; 60<span class="elsevierStyleHsp" style=""></span>mg&#44; 100<span class="elsevierStyleHsp" style=""></span>mg twice daily or 50<span class="elsevierStyleHsp" style=""></span>mg once daily&#41; or placebo&#46; The mean improvement in PASI and body surface area with respect to baseline was significantly better in all treatment groups than in the placebo group at 6 weeks&#46; The difference was dose-dependent&#46;<a class="elsevierStyleCrossRef" href="#bib0715"><span class="elsevierStyleSup">36</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">TYK2 Inhibitors</span><p id="par0105" class="elsevierStylePara elsevierViewall">Current studies focus on TYK2 inhibitors for the treatment of moderate to severe psoriasis&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">The percentage of patients who reached PASI75 at 12 weeks in a phase 2 trial &#40;267 patients&#41; was significantly greater with deucravacitinib &#40;a TYK2 inhibitor&#44; Bristol-Myers Squibb&#41; than with placebo &#40;39&#37; at 3<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h&#44; 69&#37; at 3<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&#44; 67&#37; at 6<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&#44; and 75&#37; at 12<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h vs&#46; 7&#37; in the placebo group&#41;&#46; The PASI90 response rate was 43&#37; at 12 weeks&#44; and the PASI100 response rate was 25&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0720"><span class="elsevierStyleSup">37</span></a> The ongoing phase 3 trials with this drug &#40;NCT04036435&#44;<a class="elsevierStyleCrossRef" href="#bib0725"><span class="elsevierStyleSup">38</span></a> NCT03924427<a class="elsevierStyleCrossRef" href="#bib0730"><span class="elsevierStyleSup">39</span></a>&#41; include one in which it is compared with apremilast &#40;NCT03611751<a class="elsevierStyleCrossRef" href="#bib0735"><span class="elsevierStyleSup">40</span></a>&#41;&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Brepocitinib &#40;Pfizer&#41; is a potent TYK2&#47;JAK1 inhibitor that is being evaluated for treatment of psoriasis&#46; In a phase 1 trial&#44; 30 patients with moderate to severe plaque psoriasis received 30<span class="elsevierStyleHsp" style=""></span>mg or 100<span class="elsevierStyleHsp" style=""></span>mg orally or placebo once daily for 28 days&#46; A PGA 0&#47;1 response was achieved in 57&#46;1&#37;&#44; 100&#37;&#44; and 0&#37; of cases&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0740"><span class="elsevierStyleSup">41</span></a> Topical application of brepocitinib is currently being tested in a phase 2b trial in patients with mild to moderate psoriasis &#40;NCT03850483<a class="elsevierStyleCrossRef" href="#bib0745"><span class="elsevierStyleSup">42</span></a>&#41;&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Finally&#44; another TYK2 inhibitor &#40;PF-06826647&#44; Pfizer&#41; is being investigated for moderate to severe psoriasis in a phase 2 trial &#40;NCT03895372<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">43</span></a>&#41;&#46;</p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Atopic Dermatitis</span><p id="par0125" class="elsevierStylePara elsevierViewall">Atopic dermatitis is an inflammatory skin disease with a T<span class="elsevierStyleInf">H</span>2-polarized immune response in its acute phase&#46; The JAK&#47;STAT pathway plays a key role in the dysregulation of the immune response in atopic dermatitis&#44; including overregulation of T<span class="elsevierStyleInf">H</span>2&#44; activation of eosinophils&#44; suppression of regulatory T cells&#44; and maturation of B cells&#44; with differentiation to plasma cells and secretion of immunoglobulin &#40;Ig&#41; E&#44; which binds to cutaneous mastocytes and leads to release of histamine&#46; Similarly&#44; the T<span class="elsevierStyleInf">H</span>2 response leads to release of proinflammatory cytokines and proangiogenic factors by epidermal cells&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Atopic dermatitis is associated with an increase in signaling via JAK1&#44; JAK2&#44; JAK3&#44; and TYK2<a class="elsevierStyleCrossRef" href="#bib0755"><span class="elsevierStyleSup">44</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; JAK1&#44; JAK3&#44; and STAT6 are components of IL-4 signaling that are critical for T<span class="elsevierStyleInf">H</span>2 cell differentiation<a class="elsevierStyleCrossRefs" href="#bib0760"><span class="elsevierStyleSup">45&#8211;47</span></a> and production of IL-4&#44; IL-5&#44; IL-10&#44; and IL-13&#46; STAT6 regulates the genes involved in T<span class="elsevierStyleInf">H</span>2 cells and B-cell differentiation&#44; switching from IgG to IgE&#44; and production of class II major histocompatibility complex molecules&#46; Various STAT6 polymorphisms have been associated with greater susceptibility to atopic dermatitis and high IgE levels&#46;<a class="elsevierStyleCrossRef" href="#bib0775"><span class="elsevierStyleSup">48</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0135" class="elsevierStylePara elsevierViewall">The IL-4&#47;IL-13&#47;JAK&#47;STAT pathway<a class="elsevierStyleCrossRef" href="#bib0780"><span class="elsevierStyleSup">49</span></a> is important for the integrity of the skin barrier&#46; Suppression by nonselective JAK inhibitors of STAT3 activation induced by IL-4&#47;IL-13 has been shown to improve barrier function&#44; thus promoting production of filaggrin and loricrin&#46;<a class="elsevierStyleCrossRef" href="#bib0785"><span class="elsevierStyleSup">50</span></a> Furthermore&#44; IL-4 and IL-13 play a role in pruritus through their interaction with IL-4R&#945; and JAK1 in sensory neurons&#46;<a class="elsevierStyleCrossRef" href="#bib0790"><span class="elsevierStyleSup">51</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">Factors other than IL-4 are important for differentiation of T<span class="elsevierStyleInf">H</span>2&#46; Thymic stromal lymphopoietin &#40;TSLP&#41; promotes T<span class="elsevierStyleInf">H</span>2 cell differentiation&#44; activates natural killer cells and basophils&#44; and affects maturation of B cells&#46; TSLP binds to a heterodimer composed of a TSLP receptor and an IL-7&#945; receptor and induces phosphorylation of JAK1 and JAK2&#44; leading to activation of STAT1&#44; STAT3&#44; and STAT5&#46;<a class="elsevierStyleCrossRef" href="#bib0795"><span class="elsevierStyleSup">52</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">The spleen tyrosine kinase &#40;SYK&#41; pathway is also involved in the pathogenesis of atopic dermatitis&#46; SYK is a cytoplasmic tyrosine kinase that is involved in signaling of proinflammatory cytokines and production of CCL20&#44; which attracts T<span class="elsevierStyleInf">H</span>17 cells to the skin<a class="elsevierStyleCrossRefs" href="#bib0800"><span class="elsevierStyleSup">53&#44;54</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Inhibition of SYK suppresses this activation and has an anti-inflammatory effect&#44; which may be synergetic with concomitant inhibition of JAK&#46; Favorable results have been reported for some dual inhibitors used to treat atopic dermatitis&#46;</p><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Oral Tofacitinib</span><p id="par0150" class="elsevierStylePara elsevierViewall">An open-label study of 6 patients treated with tofacitinib 5<span class="elsevierStyleHsp" style=""></span>mg once or twice daily&#44; in addition to topical treatment&#44; revealed a 36&#46;6&#37; reduction in the Scoring Atopic Dermatitis &#40;SCORAD&#41; score at weeks 8 to 12&#44; and of 12&#37; at week 29&#44; with no remarkable adverse effects&#46;<a class="elsevierStyleCrossRef" href="#bib0810"><span class="elsevierStyleSup">55</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Topical Tofacitinib</span><p id="par0155" class="elsevierStylePara elsevierViewall">Application of topical tofacitinib 2&#37; &#40;20<span class="elsevierStyleHsp" style=""></span>mg&#47;g&#41; every 12<span class="elsevierStyleHsp" style=""></span>h in 69 patients with mild to moderate atopic dermatitis for 4 weeks led to an 81&#46;7&#37; reduction in the Eczema Area and Severity Index &#40;EASI&#41; score after 4 weeks&#44; compared with 29&#46;9&#37; in patients receiving placebo&#46; The Investigator Global Assessment &#40;IGA&#41;&#44; body surface area&#44; and pruritus also improved from the first week of treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0815"><span class="elsevierStyleSup">56</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Oral Baricitinib</span><p id="par0160" class="elsevierStylePara elsevierViewall">Baricitinib &#40;Olumiant&#44; Lilly&#41; has been evaluated in a phase 2 trial and in 2 phase 3 trials for treatment of moderate to severe atopic dermatitis&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Baricitinib was used concomitantly with topical triamcinolone 0&#46;1&#37; for 16 weeks in a phase 2 trial with 124 patients&#46;<a class="elsevierStyleCrossRef" href="#bib0820"><span class="elsevierStyleSup">57</span></a> Severity of atopic dermatitis improved significantly in those who received 2<span class="elsevierStyleHsp" style=""></span>mg and 4<span class="elsevierStyleHsp" style=""></span>mg compared with placebo&#44; with a rapid improvement in pruritis during the first week and in health-related quality of life&#46; In the group treated with baricitinib 4<span class="elsevierStyleHsp" style=""></span>mg&#44; 61&#37; of patients achieved an EASI50 response at 16 weeks compared with 37&#37; in the placebo group&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">In 2 phase 3 studies in adults &#40;BREEZE-AD1 &#91;624 patients&#93; and BREEZE-AD2 &#91;615 patients&#41;&#44; baricitinib improved the severity of atopic dermatitis at 16 weeks and led to a rapid reduction in pruritus from the first week&#46; IGA 0&#47;1 was reached in BREEZE-AD1 and BREEZE-AD2 at week 16&#44; respectively&#44; in 4&#46;8&#37; and 4&#46;5&#37; of patients in the placebo group and in 11&#46;8&#37; and 8&#46;8&#37; of the groups treated with baricitinib 1<span class="elsevierStyleHsp" style=""></span>mg&#44; 11&#46;4&#37; and 10&#46;6&#37; in those treated with baricitinib 2<span class="elsevierStyleHsp" style=""></span>mg&#44; and 16&#46;8&#37; and 13&#46;8&#37; of those treated with baricitinib 4<span class="elsevierStyleHsp" style=""></span>mg&#46;<a class="elsevierStyleCrossRef" href="#bib0825"><span class="elsevierStyleSup">58</span></a> The most common adverse events were nasopharyngitis&#44; headache&#44; and increased creatine phosphokinase&#46; Long-term safety is currently being evaluated &#40;NCT03334435<a class="elsevierStyleCrossRef" href="#bib0830"><span class="elsevierStyleSup">59</span></a>&#41;&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">Baricitinib was recently approved by the European Medicines Agency for treatment of moderate to severe atopic dermatitis in adult patients who were candidates for systemic treatment&#44; with a recommended dose of 4<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#46;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">30</span></a></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Oral Upadacitinib</span><p id="par0180" class="elsevierStylePara elsevierViewall">Upadacitinib &#40;Rinvoq&#44; AbbVie&#41; is a JAK1 inhibitor that has been approved for the treatment of rheumatoid arthritis&#46;<a class="elsevierStyleCrossRef" href="#bib0835"><span class="elsevierStyleSup">60</span></a> The efficacy and safety profile of the drug in adults with moderate to severe atopic dermatitis was evaluated in a phase 2b clinical trial&#46; A total of 167 patients were randomly assigned to receive 3 different doses of upadacitinib &#40;7&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#44; 15<span class="elsevierStyleHsp" style=""></span>mg&#44; and 30<span class="elsevierStyleHsp" style=""></span>mg daily&#41; or placebo&#46; The mean percentage improvement in the EASI at week 16 over baseline was higher than for placebo at all the doses of upadacitinib &#40;39&#37; for 7&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#44; 62&#37; for 15<span class="elsevierStyleHsp" style=""></span>mg&#44; 74&#37; for 30<span class="elsevierStyleHsp" style=""></span>mg vs&#46; 23&#37; in the placebo group&#41;&#46; An EASI100 response was observed in 24&#37; of the patients treated with 30<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#44; but not in those treated with placebo&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">Results were recently published from 2 phase 3 trials&#44; Measure Up 1 and Measure Up 2&#44; which evaluate the efficacy and safety of upadacitinib for treatment of moderate to severe atopic dermatitis in adults and adolescents &#40;NCT03569293<a class="elsevierStyleCrossRef" href="#bib0840"><span class="elsevierStyleSup">61</span></a> and NCT03607422<a class="elsevierStyleCrossRef" href="#bib0845"><span class="elsevierStyleSup">62</span></a>&#41;&#46; EASI75 was achieved at 16 weeks by 70&#37; and 60&#37; of the patients who received upadacitinib 15<span class="elsevierStyleHsp" style=""></span>mg &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>281 &#91;Measure Up 1&#93; and <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>276 &#91;Measure Up 2&#93;&#41;&#44; by 80&#37; and 73&#37; of those who received upadacitinib 30<span class="elsevierStyleHsp" style=""></span>mg &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>285 &#91;Measure Up 1&#93; and <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>282 &#91;Measure Up 2&#93;&#41;&#44; and by only 16&#37; and 13&#37; in the placebo group &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>281 &#91;Measure Up 1&#93; and <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>278 &#91;Measure Up 2&#93;&#41;&#46; IGA 0&#47;1 was achieved by 48&#37; and 39&#37; of patients treated with upadacitinib 15<span class="elsevierStyleHsp" style=""></span>mg and 62&#37; and 52&#37; of those treated with upadacitinib 30<span class="elsevierStyleHsp" style=""></span>mg&#44; compared with 8&#37; and 5&#37; of the placebo groups&#46; Both doses led to an early reduction in pruritus&#44; which remained unchanged at 16 weeks&#46; The most common adverse effects were acne&#44; nasopharyngitis&#44; upper respiratory tract infection&#44; and headache&#46;<a class="elsevierStyleCrossRefs" href="#bib0850"><span class="elsevierStyleSup">63&#44;64</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">The safety and pharmacokinetics of various doses of upadacitinib are being evaluated in children with severe atopic dermatitis &#40;NCT03646604<a class="elsevierStyleCrossRef" href="#bib0860"><span class="elsevierStyleSup">65</span></a>&#41;&#44; and a phase 3 trial comparing upadacitinib with dupilimab in adults is currently underway &#40;NCT03738397<a class="elsevierStyleCrossRef" href="#bib0865"><span class="elsevierStyleSup">66</span></a>&#41;&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Oral Abrocitinib</span><p id="par0195" class="elsevierStylePara elsevierViewall">Abrocitinib may be effective and well-tolerated in patients with moderate to severe atopic dermatitis&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">A 12-week placebo-controlled phase 2b study included 269 adults treated with 4 daily doses of abrocitinib &#40;10&#44; 30&#44; 100&#44; and 200<span class="elsevierStyleHsp" style=""></span>mg&#41;&#46; The EASI improved significantly compared with placebo only for 100 and 200<span class="elsevierStyleHsp" style=""></span>mg&#47;d &#40;reduction of 59&#37; and 82&#46;6&#37; respectively vs&#46; 35&#46;2&#37; in the placebo group&#41;&#44; with a reduction in pruritus as early as day 2 of the study&#46;<a class="elsevierStyleCrossRef" href="#bib0870"><span class="elsevierStyleSup">67</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">In a recent phase 3 trial&#44; 391 adolescents and adults were treated with abrocitinib 200<span class="elsevierStyleHsp" style=""></span>mg or 100<span class="elsevierStyleHsp" style=""></span>mg or placebo over 12 weeks&#46; A greater percentage of patients in the abrocitinib 200<span class="elsevierStyleHsp" style=""></span>mg and 100<span class="elsevierStyleHsp" style=""></span>mg groups vs&#46; placebo reached IGA 0&#47;1 &#40;38&#46;1&#37; and 28&#46;4&#37; vs&#46; 9&#46;1&#37;&#44; respectively&#41;&#44; EASI75 &#40;61&#37; and 44&#46;5&#37; vs&#46; 10&#46;4&#37;&#44; respectively&#41;&#44; and EASI90 &#40;37&#46;7&#37; and 23&#46;9&#37; vs&#46; 3&#46;9&#37;&#44; respectively&#41;&#46; Adverse effects were recorded in 65&#46;8&#37; of patients who received 200<span class="elsevierStyleHsp" style=""></span>mg&#44; in 62&#46;7&#37; of the group that received 100<span class="elsevierStyleHsp" style=""></span>mg&#44; and in 53&#46;8&#37; of the placebo group&#46; The most frequent were nausea in the 200-mg group&#44; nasopharyngitis in the 100-mg group&#44; and atopic dermatitis in the placebo group&#46; Severe adverse effects were observed in the abrocitinib 200<span class="elsevierStyleHsp" style=""></span>mg&#44; 100<span class="elsevierStyleHsp" style=""></span>mg&#44; and placebo groups&#44; affecting 1&#46;3&#37;&#44; 3&#46;2&#37;&#44; and 1&#46;3&#37; of patients&#44; respectively&#46; The effects considered to be associated with treatment included 1 case of herpangina and 1 case of pneumonia in the abrocitinib 100-mg group&#46; Two patients in the abrocitinib 200-mg group developed herpes zoster&#44; and 2 patients in the abrocitinib 100-mg group developed eczema herpeticum&#46; Furthermore&#44; in the group treated with 200<span class="elsevierStyleHsp" style=""></span>mg&#44; the platelet count decreased in 2 patients&#44; and thrombocytopenia was detected in 5 patients&#46;<a class="elsevierStyleCrossRef" href="#bib0875"><span class="elsevierStyleSup">68</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">The long-term safety and efficacy profile of abrocitinib is being studied in adolescents &#40;NCT03796676&#44;<a class="elsevierStyleCrossRef" href="#bib0880"><span class="elsevierStyleSup">69</span></a> NCT03627767&#44;<a class="elsevierStyleCrossRef" href="#bib0885"><span class="elsevierStyleSup">70</span></a> NCT03422822&#44;<a class="elsevierStyleCrossRef" href="#bib0890"><span class="elsevierStyleSup">71</span></a>&#41;&#46; Ongoing studies are comparing the efficacy of oral abrocitinib with subcutaneous dupilumab in adults with atopic dermatitis &#40;NCT04345367&#44;<a class="elsevierStyleCrossRef" href="#bib0895"><span class="elsevierStyleSup">72</span></a> NCT03720470<a class="elsevierStyleCrossRef" href="#bib0900"><span class="elsevierStyleSup">73</span></a>&#41;&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Oral Gusacitinib</span><p id="par0215" class="elsevierStylePara elsevierViewall">Gusacitinib &#40;Asana BioSciences&#41; is a dual inhibitor of the JAK and SYK pathways that is currently being trialed as oral medication&#46; In a phase 1b trial involving 36 patients&#44; EASI50 was achieved and pruritis decreased in almost all patients at 4 weeks of treatment with 20&#44; 40&#44; or 80<span class="elsevierStyleHsp" style=""></span>mg&#46; An EASI75 response was achieved in 63&#37; of patients treated with 40<span class="elsevierStyleHsp" style=""></span>mg and in 50&#37; of those treated with 80<span class="elsevierStyleHsp" style=""></span>mg&#47;d compared with 22&#37; in the placebo group&#46; The improvement in the EASI response was associated with a decrease in the levels of the cutaneous biomarkers T<span class="elsevierStyleInf">H</span>2 and T<span class="elsevierStyleInf">H</span>22&#46;<a class="elsevierStyleCrossRef" href="#bib0905"><span class="elsevierStyleSup">74</span></a></p><p id="par0220" class="elsevierStylePara elsevierViewall">Results are pending from a phase 2b placebo-controlled trial to evaluate the efficacy and safety of ASN002 in 220 patients with moderate to severe atopic dermatitis &#40;NCT03531957<a class="elsevierStyleCrossRef" href="#bib0910"><span class="elsevierStyleSup">75</span></a>&#41;&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Topical Ruxolitinib</span><p id="par0225" class="elsevierStylePara elsevierViewall">In a phase 2b trial&#44;<a class="elsevierStyleCrossRef" href="#bib0915"><span class="elsevierStyleSup">76</span></a> 307 patients with mild to moderate atopic dermatitis were randomized to receive ruxolitinib cream 1&#46;5&#37;&#47;12<span class="elsevierStyleHsp" style=""></span>h&#44; 1&#46;5&#37;&#47;24<span class="elsevierStyleHsp" style=""></span>h&#44; 0&#46;5&#37;&#47;24<span class="elsevierStyleHsp" style=""></span>h&#44; or 0&#46;15&#37;&#47;24<span class="elsevierStyleHsp" style=""></span>h for 8 weeks&#44; vehicle&#44; or acetonide triamcinolone 0&#46;1&#37; cream every 12<span class="elsevierStyleHsp" style=""></span>hours for 4 weeks&#46; A therapeutic benefit was recorded for all of the ruxolitinib regimens at week 4&#44; although the regimen that led to the greatest change in EASI was ruxolitinib 1&#46;5&#37;&#47;12<span class="elsevierStyleHsp" style=""></span>h &#40;71&#46;6&#37; vs&#46; 15&#46;5&#37; for vehicle&#41;&#46; The improvement in EASI was greater in patients treated with ruxolitinib 1&#46;5&#37; every 12<span class="elsevierStyleHsp" style=""></span>hours or every 24<span class="elsevierStyleHsp" style=""></span>hours than in those treated with triamcinolone 0&#46;1&#37;&#44; although the differences were not statistically significant&#46; Furthermore&#44; ruxolitinib managed to improve pruritis quickly&#46; The improvement was maintained&#44; the drug was well tolerated&#44; and no relevant reactions were observed at the application site&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">A phase 1 trial is currently evaluating the safety and pharmacokinetics of topical ruxolitinib in pediatric patients &#40;NCT03257644<a class="elsevierStyleCrossRef" href="#bib0920"><span class="elsevierStyleSup">77</span></a>&#41;&#44; and other phase 3 trials include adolescents &#40;NCT03745638&#44;<a class="elsevierStyleCrossRef" href="#bib0925"><span class="elsevierStyleSup">78</span></a> NCT03745651<a class="elsevierStyleCrossRef" href="#bib0930"><span class="elsevierStyleSup">79</span></a>&#41;&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Topical Delgocitinib</span><p id="par0235" class="elsevierStylePara elsevierViewall">The JAK1&#44; JAK2&#44; and JAK3 inhibitor delgocitinib &#40;Corectim&#44; Japan Tobacco&#47;LEO Pharma&#41; was developed for topical treatment of atopic dermatitis&#46;<a class="elsevierStyleCrossRef" href="#bib0935"><span class="elsevierStyleSup">80</span></a> Phase 1 and 2 studies<a class="elsevierStyleCrossRefs" href="#bib0940"><span class="elsevierStyleSup">81&#44;82</span></a> proved the concept of therapeutic efficacy with respect to severity and pruritus&#46; Pruritus improved 1 day after initiating delgocitinib&#44; probably owing to the inhibition of IL-31&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">Results were recently published from a study that evaluated the safety and efficacy profile of delgocitinib 0&#46;5&#37; ointment in 158 Japanese patients aged &#8805;16 years with moderate to severe atopic dermatitis&#46; The mean percentage change in EASI after 4 weeks was &#8722;44&#46;3&#37; in the delgocitinib group and 1&#46;7&#37; in the vehicle group&#59; the results remained unchanged at 24 weeks&#46; Various adverse effects were recorded&#44; although these were mainly mild&#44; affecting 4&#46;7&#37; of patients in the delgocitinib group and 1&#46;9&#37; in the vehicle group&#46; The most common adverse effect was nasopharyngitis&#44; followed by Kaposi varicelliform eruption and acne&#46;<a class="elsevierStyleCrossRef" href="#bib0950"><span class="elsevierStyleSup">83</span></a></p><p id="par0245" class="elsevierStylePara elsevierViewall">Topical delgocitinib 0&#46;5&#37; &#40;Corectim&#41; has been approved in Japan for treatment of atopic dermatitis&#46;<a class="elsevierStyleCrossRef" href="#bib0955"><span class="elsevierStyleSup">84</span></a> Ongoing studies are evaluating various concentrations &#40;NCT03725722<a class="elsevierStyleCrossRef" href="#bib0960"><span class="elsevierStyleSup">85</span></a>&#41; and include pediatric patients &#40;NCT03826901<a class="elsevierStyleCrossRef" href="#bib0965"><span class="elsevierStyleSup">86</span></a>&#41;&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Other Options</span><p id="par0250" class="elsevierStylePara elsevierViewall">An ongoing study is evaluating the safety and efficacy profile of the JAK1 inhibitor SHR0302 &#40;NCT04162899<a class="elsevierStyleCrossRef" href="#bib0970"><span class="elsevierStyleSup">87</span></a>&#41; for treatment of patients with moderate to severe atopic dermatitis&#46; Results are pending from another study with topical brepocitinib for treatment of mild to moderate atopic dermatitis &#40;NCT03903822&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0975"><span class="elsevierStyleSup">88</span></a></p></span></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Other Applications in Dermatology</span><p id="par0255" class="elsevierStylePara elsevierViewall">JAK inhibitors were recently used for the treatment of other treatment-refractory dermatologic conditions in which activation of the JAK&#47;STAT pathway plays a key role &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Conclusions</span><p id="par0260" class="elsevierStylePara elsevierViewall">Dysregulation of the JAK&#47;STAT pathway could intervene in the pathogenesis of many dermatologic diseases&#44; including vitiligo&#44; alopecia areata&#44; psoriasis&#44; and atopic dermatitis&#46; JAK inhibitors&#44; which have an acceptable safety profile&#44; could be used for the simultaneous treatment of pathogenically similar inflammatory skin diseases with common signaling pathways&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">In the case of moderate to severe psoriasis&#44; tofacitinib has been evaluated in phase 1&#44; 2&#44; and 3 trials&#44; all of which show it to be efficacious&#44; especially at 10<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&#44; although the drug has not been approved by regulatory committees&#46; Recent data suggest that TYK2 inhibitors could show promising results for the treatment of psoriasis&#46; One such drug&#44; deucravacitinib&#44; has shown maximum efficacy for oral treatment of psoriasis&#46; Current therapeutic options in atopic dermatitis are limited&#44; although oral and topical JAK inhibitors have yielded promising results&#44; with improvement in the severity of atopic dermatitis and a rapid and marked improvement in pruritus and quality of life&#46; Baricitinib was recently approved for the treatment of moderate to severe atopic dermatitis in adults&#46;</p><p id="par0270" class="elsevierStylePara elsevierViewall">In the future&#44; JAK inhibitors could prove to be a real alternative therapy for some inflammatory skin diseases&#46; Selective inhibitors have a superior safety and efficacy profile&#44; whereas nonselective inhibitors are being developed mainly for topical use&#46; The inhibition of multiple signals&#44; especially the response to interferon&#44; could increase susceptibility to infection and viral reactivation&#46; While the safety and efficacy profile seems favorable for the moment&#44; more studies are necessary to determine the doses that will optimize efficacy&#44; cost-effectiveness&#44; and safety of this drug family for potential use in skin conditions in the long term&#46;</p></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Conflicts of Interest</span><p id="par0275" class="elsevierStylePara elsevierViewall">C&#46; Garcia-Melendo declares that she has no conflicts of interest&#46;</p><p id="par0280" class="elsevierStylePara elsevierViewall">X&#46; Cubir&#243; has received fees from Novartis&#44; Leo-Pharma&#44; and Almirall&#46;</p><p id="par0285" class="elsevierStylePara elsevierViewall">L&#46; Puig has received fees and&#47;or has participated in clinical trials sponsored by AbbVie&#44; Almirall&#44; Amgen&#44; Baxalta&#44; Biogen&#44; Boehringer Ingelheim&#44; Celgene&#44; Gebro&#44; Janssen&#44; JS BIOCAD&#44; Leo-Pharma&#44; Lilly&#44; Merck-Serono&#44; MSD&#44; Mylan&#44; Novartis&#44; Pfizer&#44; Regeneron&#44; Roche&#44; Sandoz&#44; Samsung-Bioepis&#44; Sanofi&#44; and UCB&#46;</p></span></span>"
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          "titulo" => "Palabras clave"
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        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
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          "identificador" => "sec0010"
          "titulo" => "Psoriasis"
          "secciones" => array:9 [
            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Oral Tofacitinib"
            ]
            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Topical Tofacitinib"
            ]
            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Topical Ruxolitinib"
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            3 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Oral Baricitinib"
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            4 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "Oral Abrocitinib"
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            5 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Oral Solcitinib"
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            6 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Oral Itacitinib Adipate"
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            7 => array:2 [
              "identificador" => "sec0050"
              "titulo" => "Oral Peficitinib"
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            8 => array:2 [
              "identificador" => "sec0055"
              "titulo" => "TYK2 Inhibitors"
            ]
          ]
        ]
        6 => array:3 [
          "identificador" => "sec0060"
          "titulo" => "Atopic Dermatitis"
          "secciones" => array:9 [
            0 => array:2 [
              "identificador" => "sec0065"
              "titulo" => "Oral Tofacitinib"
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            1 => array:2 [
              "identificador" => "sec0070"
              "titulo" => "Topical Tofacitinib"
            ]
            2 => array:2 [
              "identificador" => "sec0075"
              "titulo" => "Oral Baricitinib"
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            3 => array:2 [
              "identificador" => "sec0080"
              "titulo" => "Oral Upadacitinib"
            ]
            4 => array:2 [
              "identificador" => "sec0085"
              "titulo" => "Oral Abrocitinib"
            ]
            5 => array:2 [
              "identificador" => "sec0090"
              "titulo" => "Oral Gusacitinib"
            ]
            6 => array:2 [
              "identificador" => "sec0095"
              "titulo" => "Topical Ruxolitinib"
            ]
            7 => array:2 [
              "identificador" => "sec0100"
              "titulo" => "Topical Delgocitinib"
            ]
            8 => array:2 [
              "identificador" => "sec0105"
              "titulo" => "Other Options"
            ]
          ]
        ]
        7 => array:2 [
          "identificador" => "sec0110"
          "titulo" => "Other Applications in Dermatology"
        ]
        8 => array:2 [
          "identificador" => "sec0115"
          "titulo" => "Conclusions"
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        9 => array:2 [
          "identificador" => "sec0120"
          "titulo" => "Conflicts of Interest"
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          "titulo" => "References"
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    "pdfFichero" => "main.pdf"
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    "fechaRecibido" => "2020-09-30"
    "fechaAceptado" => "2020-12-21"
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          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1395149"
          "palabras" => array:4 [
            0 => "JAK&#47;STAT pathway"
            1 => "Janus kinase inhibitors"
            2 => "Psoriasis"
            3 => "Atopic dermatitis"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1395148"
          "palabras" => array:4 [
            0 => "JAK&#47;STAT"
            1 => "Inhibidores de JAK"
            2 => "Psoriasis"
            3 => "Dermatitis at&#243;pica"
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    "resumen" => array:2 [
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Dermatologists&#8217; interest in the Janus-associated kinase &#40;JAK&#41;&#47;signal transducers and activators of transcription &#40;STAT&#41; pathway has been growing as evidence builds to support its key role in the pathogenesis of inflammatory skin diseases&#46; Because certain proinflammatory cytokines use the JAK&#47;STAT pathway for signal transduction&#44; it has become a promising therapeutic target in diseases where selective modulation of the immune system can be useful&#46; We aim to review current knowledge of the JAK&#47;STAT signaling pathway and its role in immune-mediated skin diseases&#46; In the second part of the review we cover the efficacy and safety of oral and topical JAK inhibitors in the treatment of psoriasis&#44; atopic dermatitis&#44; and other skin diseases&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La v&#237;a de se&#241;alizaci&#243;n de citocinas Janus cinasa&#47;transductor de se&#241;al y activador de transcripci&#243;n &#40;JAK&#47;STAT&#41; es un &#225;rea de inter&#233;s emergente en dermatolog&#237;a&#44; con evidencia creciente del papel clave en la patog&#233;nesis de las enfermedades inflamatorias cut&#225;neas&#46; Debido a que algunas citocinas proinflamatorias usan la v&#237;a JAK&#47;STAT para la transducci&#243;n de se&#241;ales se convierte en una diana terap&#233;utica prometedora para el tratamiento de dichas enfermedades al modular de forma selectiva el sistema inmune&#46; El objetivo de esta revisi&#243;n es conocer la v&#237;a de se&#241;alizaci&#243;n JAK&#47;STAT y su papel en distintas enfermedades dermatol&#243;gicas inmunomediadas&#46; En esta segunda parte&#44; se revisar&#225; la eficacia y seguridad de los inhibidores de JAK &#8211;en formulaci&#243;n oral o t&#243;pica&#8211; para el tratamiento de la psoriasis&#44; la dermatitis at&#243;pica y otras dermatosis&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as&#58; Garcia-Melendo C&#44; Cubir&#243; X&#44; Puig L&#46; Inhibidores de JAK&#58; usos en dermatolog&#237;a&#46; Parte 2&#58; aplicaciones en psoriasis&#44; dermatitis at&#243;pica y otras dermatosis&#46; Actas Dermosifiliogr&#46; 2021&#59;112&#58;586&#8211;600&#46;</p>"
      ]
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        "etiqueta" => "Figure 1"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">IL-4&#47;IL-13&#47;JAK&#47;STAT signaling pathway and SYK pathway in atopic dermatitis&#46;</p> <p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The figure shows various JAK inhibitors and dual JAK&#47;SYK inhibitors in atopic dermatitis&#46; The biological functions of IL-4 and IL-13 are mediated by their binding to the subunits IL-4R&#945; and IL-13R&#945;1 of the corresponding receptors&#46; IL-4 binds to a type 1 receptor that includes IL-4R&#945; and the &#947; chain of the cytokine receptor or a type 2 receptor configured by IL-4R&#945; and IL-13R &#945;1&#46; The latter is the main IL-13 receptor&#46;</p> <p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">IL-5 produced as a result of polarization of type 2 helper T cells binds to the IL-5R&#945; subunit of its receptor to form a complex with a shared signaling subunit&#44; the &#946; chain&#44; and induce phosphorylation of JAK1&#47;JAK2 and activation of STAT1&#44; STAT3&#44; and STAT5&#46;</p> <p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Via its SH2 domains&#44; SYK binds to diphosphorylated immunoreceptor tyrosine-based activation motifs &#40;ITAM&#41; in the cytoplasm of various immune receptors&#44; such as T-&#44; B-&#44; NK-cell receptors or the various receptors for the constant fraction of immunoglobulin &#40;Fc&#41; in neutrophils&#44; mastocytes&#44; macrophages dendritic cells&#44; and other strains of the immune system&#46; This interaction results in the activation of other proteins that transmit downstream signals&#46;</p> <p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Figure generated with the assistance of Biorender&#46;com&#46;</p>"
        ]
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        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
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          "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Ongoing trials&#58; information from ClinicalTrials&#46;gov&#46;<a class="elsevierStyleCrossRef" href="#bib1070"><span class="elsevierStyleSup">107</span></a></p><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#46; CDASI&#44; Cutaneous Dermatomyositis Disease Area and Severity Index&#59; CK&#44; creatine kinase&#59; CLASI&#44; Cutaneous Lupus Erythematosus Disease Area and Severity Index&#59; CMV&#44; cytomegalovirus&#59; CSAMI&#44; cutaneous sarcoidosis activity and morphology instrument&#59; DM&#44; dermatomyositis&#59; GVHD&#44; graft-versus-host disease&#59; HCQ&#44; hydroxychloroquine&#59; HS&#44; hidradenitis suppurativa&#59; SLE&#44; systemic lupus erythematosus&#59; LPPAI&#44; Lichen Planopilaris Activity Index&#59; MMF&#44; mycophenolate mofetil&#59; MTX&#44; methotrexate&#59; PDN&#44; prednisone&#59; PG&#44; pyoderma gangrenosum&#59; SLEDAI-2K&#44; Systemic Lupus Erythematosus Disease Activity Index-2000&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">JAK Inhibitor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Outcome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Safety&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowgroup " rowspan="6" align="left" valign="\n
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                  \t\t\t\t">Dermatomyositis</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowgroup " rowspan="3" align="left" valign="\n
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                  \t\t\t\t">Oral tofacitinib</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Kurtzman et al&#46; &#40;2016&#41;<a class="elsevierStyleCrossRef" href="#bib0980"><span class="elsevierStyleSup">89</span></a>- <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3 &#40;2 with classic DM and 1 with amyopathic DM&#41;- Tofacitinib 5&#8211;10<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h &#40;1 patient received concomitant hydroxychloroquine&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">- Clinical response at 4 wk- Mean treatment period&#44; 9&#46;6 mo- Mean improvement in CDASI score&#44; 12 points- Pruritus improved in all patients- Strength and fatigue improved in all patients with classic DM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">No adverse effects reported&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Wendel et al&#46; &#40;2019&#41;<a class="elsevierStyleCrossRef" href="#bib0985"><span class="elsevierStyleSup">90</span></a>- <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2- Patient A&#58; Classic DM with muscular and subcutaneous calcifications&#46; Treated with tofacitinib 5<span class="elsevierStyleHsp" style=""></span>mg&#47;12h<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MTX 12&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;wk<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>PDN 5<span class="elsevierStyleHsp" style=""></span>mg&#47;d- Patient B&#58; Classic DM with calcifications and interstitial lung disease&#46; CDASI 25&#46; Treated with tofacitinib 5<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">- Patient A&#58; Stabilization of calcifications at 2 wk&#46; Calcifications stable or regressing at week 28&#44; with no acral ulcers- Patient B&#58; Improvement in respiratory&#44; cutaneous&#44; and musculoskeletal symptoms&#46; CDASI 10 at 12 wk&#46; CDASI 3 at 28 wk&#44; with no new calcifications and improvement or stabilization of previous calcifications&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">- Patient A&#58; Transient and moderate hypercalcinemia&#44; weight gain- Patient B&#58; Weight gain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NCT03002649<a class="elsevierStyleCrossRef" href="#bib0990"><span class="elsevierStyleSup">91</span></a>- Phase 11- <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10- Patients with refractory DM- Tofacitinib 11<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h&#44; 12 wk of treatment with an extension of 4 wk&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No results available&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No results available&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowgroup " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Oral ruxolitinib</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hornung et al&#46; &#40;2014&#41;<a class="elsevierStyleCrossRef" href="#bib0995"><span class="elsevierStyleSup">92</span></a>- <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1- Classic DM&#44; CDASI<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>30- Ruxolitinib 15<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">- CDASI<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0 at 2 mo -Recovery of muscle strength&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No adverse effects reported&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fetter et al&#46; &#40;2020&#41;<a class="elsevierStyleCrossRef" href="#bib1000"><span class="elsevierStyleSup">93</span></a>- <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1- Six-year history of classic DM <span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>10-year history of alopecia areata- Ruxolitinib 10<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h<span class="elsevierStyleHsp" style=""></span>&#8594;<span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">- Improvement in muscle pain&#44; muscle strength&#44; and skin lesions of DM at 4 mo&#46; Regrowth of hair and eyebrows&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No adverse effects reported&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Jalles et al&#46; &#40;2020&#41;<a class="elsevierStyleCrossRef" href="#bib1005"><span class="elsevierStyleSup">94</span></a>- <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1- Classic DM&#44; with MDA5<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>and rapidly progressive interstitial pneumonia- Ruxolitinib 15<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>corticosteroids 4<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">- Stabilization of symptoms at 9 mo&#44; with no signs of disease activity affecting the muscles&#44; lungs&#44; or skin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Development of small cell lung carcinoma&#46; Discontinuation of ruxolitinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_colgroup " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowgroup " rowspan="7" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cutaneous GVHD</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowgroup " rowspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Oral ruxolitinib</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Spoerl et al&#46; &#40;2014&#41;<a class="elsevierStyleCrossRef" href="#bib1010"><span class="elsevierStyleSup">95</span></a>- <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4- Patients with cutaneous GVHD refractory to 2 previous immunosuppressants and corticosteroids&#46; Area affected 50&#37;- Oral ruxolitinib 10<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">- Reduction of the affected area to<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>25&#37;- Response in 1 wk and 1&#46;5 wk&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No adverse effects reported&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Zeiser et al&#46; &#40;2015&#41;<a class="elsevierStyleCrossRef" href="#bib1015"><span class="elsevierStyleSup">96</span></a>- Retrospective study of 19 centers in Europe and the USA&#46;- 95 patients with corticosteroid-refractory GVHD &#40;acute GVHD <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>54&#44; chronic GVHD <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>41&#41;&#44; all moderate to severe&#46;- Ruxolitinib 5&#8211;10<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">- Acute GVHD&#58; the global response rate was 81&#46;5&#37; &#40;44&#47;54&#41;&#44; including 25 complete responses &#40;46&#46;3&#37;&#41;&#46; Median time to response&#44; 1&#46;5 wk&#46;- Chronic GVHD&#58; overall response rate&#44; 85&#46;4&#37; &#40;35&#47;41&#41;&#59; partial response 78&#37; &#40;32&#47;41&#41;&#59; and complete response&#44; 7&#46;3&#37; &#40;3&#47;41&#41;&#46; Median time to response&#44; 3 wk&#46;- Very satisfactory response in patients with skin involvement&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cytopenia &#40;55&#46;6&#37; in the acute GVHD group and 17&#46;1&#37; in the chronic GVHD group&#41;Reactivation of CMV &#40;33&#46;3&#37; in acute GVHD and 14&#46;6&#37; chronic GVHD&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sarmiento et al&#46; &#40;2017&#41;<a class="elsevierStyleCrossRef" href="#bib1020"><span class="elsevierStyleSup">97</span></a>- <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8- GVHD refractory to corticosteroids and extracorporeal photopheresis&#46; Acute GVHD&#44; 3 patients &#40;1 pulmonary&#44; 2 cutaneous&#44; 1 multisystemic&#41;&#59; chronic GVHD&#44; 5 patients &#40;3 cutaneous&#41;- Oral ruxolitinib&#44; 10&#8211;20<span class="elsevierStyleHsp" style=""></span>mg&#47;d&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Response in 85&#37; and complete response in 50&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2 patients required dose reduction owing to grade 2 neutropenia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ongoing trials&#58;- Phase 2&#58; NCT03491215NCT02953678NCT03616184- Phase 3&#58;NCT02913261NCT03112603&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No results available&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No results available&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Oral itacitinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ongoing trialsPhase 1&#58; NCT03497273Phase 2&#58; NCT03846479Phase 3&#58; NCT03584516&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No results available&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No results available&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Topical ruxolitinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ongoing trialsPhase 2 NCT03395340&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No results available&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No results available&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Oral baricitinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ongoing trialsPhase 1&#47;2&#58; NCT02759731&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No results available&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No results available&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_colgroup " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hidradenitis suppurativa</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Oral tofacitinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Savage et al&#46; &#40;2020&#41;<a class="elsevierStyleCrossRef" href="#bib1025"><span class="elsevierStyleSup">98</span></a>- <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2- Patient A&#58; Hurley stage III HS&#46; Treated with tofacitinib 5<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>amoxicillin 500<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>ciclosporin 5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg- Patient B&#58; Hurley stage III HS&#46; Tofacitinib 5<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>amoxicillin-clavulanate 3 wk<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>azithromycin 1 wk<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MMF 1250<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>topical corticosteroids&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">- Patient A&#58; Reduced pain and number of lesions at 4 mo&#44; enabling dose of ciclosporin to be reduced&#46; No pain at 11 mo&#44; with persistence only of inactive lesions- Patient B&#58; Reduction in number of admissions&#44; improvement in ulcers&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">- Patient A&#46; No adverse effects- Patient B&#58; Herpes zoster 3 y after initiation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Oral INCB054707 &#40;JAK1 inhibitor&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ongoing trialsPhase 2&#58;NCT03607487NCT03569371&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No results available&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No results available&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_colgroup " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowgroup " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lichen planus</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Oral tofacitinib</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yang et al&#46; &#40;2018&#41;<a class="elsevierStyleCrossRef" href="#bib1030"><span class="elsevierStyleSup">99</span></a>- Lichen planopilaris <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10- Tofacitinib 10&#8211;15<span class="elsevierStyleHsp" style=""></span>mg&#47;d for 2&#8211;19 mo- Adjuvant treatment&#58; intralesional triamcinolone &#40;2 patients&#41;&#44; HCQ &#40;1 patient&#41;&#44; intralesional triamcinolone <span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HCQ &#40;1 patient&#41;&#44; intralesional triamcinolone<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>tacrolimus ointment &#40;1 patient&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">- Clinical response in 8 patients &#40;4 in monotherapy and 4 with adjuvant therapy&#41;- LPPAI 6&#46;22 at baseline and 3&#46;08 after treatment&#46; Reduction in LPPAI score of 30&#37;-94&#37;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Weight gain in 1 patient &#40;4&#46;5<span class="elsevierStyleHsp" style=""></span>kg at 12 mo&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Damsky et al&#46; &#40;2020&#41;<a class="elsevierStyleCrossRef" href="#bib1035"><span class="elsevierStyleSup">100</span></a>- <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3 with erosive lichen planus refractory to previous treatments &#40;patient 1&#58; prednisone&#44; methylprednisolone&#59; patient 2&#58; methotrexate&#44; mycophenolate mofetil&#44; ciclosporin&#59; patient 3&#58; prednisone&#44; acitretin&#41;&#46;- Tofacitinib 5<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h- Patient 1 received adjuvant therapy with MTX and PDN 10<span class="elsevierStyleHsp" style=""></span>mg daily&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">- Patient A&#58; Remission of symptoms and lesions Recurrence on suspending tofacitinib and MTX&#44; improvement when tofacitinib was reintroduced- Patient B&#58; Resolution of pain and bleeding&#46; Remission of lesions&#46;- Patient C&#58; Resolution of pain&#46; Remission of lesions&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No adverse effects reported&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Topical ruxolitinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ongoing trialsPhase 2 NCT03697460&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No results available&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No results available&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_colgroup " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowgroup " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cutaneous lupus erythematosus</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Oral ruxolitinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Wenzel et al&#46; &#40;2016&#41;<a class="elsevierStyleCrossRef" href="#bib1040"><span class="elsevierStyleSup">101</span></a>- <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1Patient with primary myelofibrosis and chilblain lupus-Ruxolitinib 20<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Complete remission of skin lesions at 4 mo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No adverse effects reported&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Baricitinib oral&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Wallace et al&#46; &#40;2018&#41;<a class="elsevierStyleCrossRef" href="#bib1045"><span class="elsevierStyleSup">102</span></a>- Phase 2 trial&#44; 24 wk- <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>314&#44; randomized to placebo&#44; baricitinib 2<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#44; or baricitinib 4<span class="elsevierStyleHsp" style=""></span>mg&#47;d &#40;1&#58;1&#58;1&#41;- Patients with SLE&#46; Mucocutaneous activity measured by SLEDAI-2K in 84&#37;&#44; although CLASI low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No significant improvement observed in skin lesions&#46;Baseline CLASI 4&#46;2&#44; which is probably not sufficient to reveal differences between the placebo and treatment groups&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Severe infection in 6&#37; of the baricitinib 4<span class="elsevierStyleHsp" style=""></span>mg group&#44; 2&#37; of the 2<span class="elsevierStyleHsp" style=""></span>mg group&#44; and 1&#37; of the placebo group&#46;Baricitinib led to dose-dependent reductions in hemoglobin&#44; neutrophil&#44; and triglyceride values and increase in platelet&#44; CK&#44; HDL cholesterol&#44; and total cholesterol values&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Oral tofacitinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ongoing trialsPhase 1&#58; NCT03159936&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No results available&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No results available&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_colgroup " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Chronic hand eczema&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Topical delgocitinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ongoing trialsPhase 2&#58;NCT03683719NCT02664805&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No results available&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No results available&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_colgroup " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowgroup " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pyoderma gangrenosum</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowgroup " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Oral tofacitinib</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Gregory et al&#46; &#40;2019&#41;<a class="elsevierStyleCrossRef" href="#bib1050"><span class="elsevierStyleSup">103</span></a>- <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;- Oral tofacitinib 10<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>infliximab 10<span class="elsevierStyleHsp" style=""></span>mg&#47;kg &#40;every 4<span class="elsevierStyleHsp" style=""></span>wk&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lesion almost completely healed 3 wk after adding tofacitinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No adverse effects reported&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Kochar et al&#46; &#40;2019&#41;<a class="elsevierStyleCrossRef" href="#bib1055"><span class="elsevierStyleSup">104</span></a>- <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#46; Crohn disease and refractory PG- Treated with tofacitinib 5&#8211;10<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h for severe inflammatory arthritis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">- Patient A&#58; Improvement at 2 wk&#44; resolution of PG at 12 wk- Patient B&#58; PG completely healed at 12 wk- Patient C&#58; Lesions improved at 1 mo&#44; although the dose had to be increased to 10<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h for complete resolution&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No adverse effects reported&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Oral ruxolitinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nasifoglu et al&#46; &#40;2018&#41;<a class="elsevierStyleCrossRef" href="#bib1060"><span class="elsevierStyleSup">105</span></a>- <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1- Concomitant polycythemia vera with mutated JAK2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Rapid improvement in PG and disappearance of lesion at 4 y&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No adverse effects reported&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cutaneous sarcoidosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Oral tofacitinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Damsky et al&#46; &#40;2019&#41;<a class="elsevierStyleCrossRef" href="#bib1065"><span class="elsevierStyleSup">106</span></a>- <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3- Tofacitinib 5<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Complete response in 2 patientsOne patient lost to follow-up after a 96&#37; in CSAMI at 4 mo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No adverse effects reported&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Granuloma annulare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Oral tofacitinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Damsky et al&#46; &#40;2019&#41;<a class="elsevierStyleCrossRef" href="#bib1065"><span class="elsevierStyleSup">106</span></a>- <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1- Tofacitinib 5<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Complete response&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No adverse effects reported&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">The table shows the studies performed or underway with JAK inhibitors for the treatment of various skin conditions&#44; the main results obtained&#44; and the safety of the drugs&#46; Available evidence for JAK inhibitors is based mainly on case series&#44; although clinical trials are ongoing&#46;</p>"
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          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Use of JAK Inhibitors in Other Skin Conditions<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a></p>"
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Article information

ISSN: 15782190
Original language: English

DOI:10.1016/j.adengl.2021.05.008

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