With the development and market introduction of biologics, much progress has been made in recent years in the systemic treatment of psoriasis. Currently, targeted therapy with antibodies against IL-17 or IL-23 exhibits high efficacy and allows complete or almost complete clinical clearance of psoriasis lesions in a high percentage of cases (Blauvelt et al., 2017; Langley et al., 2014; Papp et al., 2017; Reich et al., 2018). However, patients with limited body area involvement (i.e. mild forms of psoriasis) who represent the majority of psoriasis patients with up to 90% (Stern et al., 2004) have been neglected. Not much innovation has occurred in the past few years on topical treatment of psoriasis that is mainly prescribed to these patients. Steroids, vitamin D3 and vitamin A analogues are most commonly used as topical agents in such patients, but besides changes in their pharmaceutical formulation, they have not been developed further in recent years (de Korte et al., 2008; Krueger et al., 2001; Langley et al., 2011; Schaarschmidt et al., 2015). Short courses of dithranol (1,8-dihydroxy-9-anthracenone or anthralin) have been successfully used as intermittent topical treatment of psoriasis since 1916 (Nast et al., 2012; Sehgal et al., 2014; Vleuten et al., 1996). Despite its numerous disadvantages like brown staining and irritation of perilesional skin, dithranol has remained one of the most effective topical treatment modalities in psoriasis. Analogous to the most recent generation of biologics (including anti-IL-17 and anti-IL-23 antibodies), dithranol delivers PASI75 rates in 66–82.5% of patients with fast action and clearance of skin lesion within very few weeks (Kemény et al., 1990; Painsi et al., 2015b; Sehgal et al., 2014; van de Kerkhof, 2015). Although dithranol has been used for many years, its exact mechanism of action has remained largely unknown (Holstein et al., 2017; Kemény et al., 1990; Kucharekova et al., 2006; Sehgal et al., 2014).

With the aim of unraveling dithranol’s therapeutic mechanisms and to possibly uncover new targets for topical treatment of psoriasis, we conducted a clinical trial and employed several mouse models including the c-Jun/JunB knockout model (Zenz et al., 2005) and the imiquimod psoriasis model (van der Fits et al., 2009) in order to address this issue and elucidate dithranol's effects. In this study, we demonstrate that dithranol exerts its anti-psoriatic effects by directly targeting keratinocytes and their crosstalk with neutrophils, as well as disrupting the IL-36 inflammatory loop. Consistent with this finding, we observed that dithranol’s therapeutic activity was completely independent of its pro-inflammatory effect mainly on perilesional skin, thus overthrowing the long-believed paradigm that dithranol-induced irritation is crucial for its anti-psoriatic action and unraveling irritation merely as a bystander effect of treatment.

This study demonstrates that topical dithranol directly targets keratinocytes (in particular their differentiation regulators and AMPs), keratinocyte-neutrophil crosstalk and inhibits the IL-36 inflammatory loop in psoriasis, thus unraveling after over 100 years of use, the therapeutic mechanism of one of the most effective topical treatments of psoriasis. Dithranol significantly diminished mRNA expression of pro-psoriatic IL-1 family members (IL36A, IL36G and IL36RN) (Supplementary file 1 and Figure 4). At day 6 after start of dithranol treatment, PASI had decreased by 33%, but at week 2–3 we saw a reduction of 58%, an effect that was paralleled by reduced expression of IL-36-related genes in psoriasis patients. The therapeutic importance of reduction of IL-1 family members in human skin was substantiated by results generated in the keratinocyte-based c-Jun/JunB mouse psoriasis model (Zenz et al., 2005). Expression of IL36RN (murine Il1f5) and IL36B (Il1f8) was significantly reduced in dithranol-treated psoriatic c-Jun/JunB lesions compared to controls (Figure 4) and among the top differentially expressed genes in our human and mouse dataset were genes involved in keratinocyte and epidermal differentiation (Table 4, Table 7). Dithranol strongly reduced mRNA expression of the keratinocyte differentiation regulator involucrin (IVL) and members of the serpin family (SERPBINB7, SERBINB13) both in lesional skin of patients and c-Jun/JunB knockout mice (Figure 4). Moreover, dithranol downregulated expression of AMPs such as ß-defensins (DEFB4A and DEFB4B) produced by keratinocytes (Liu et al., 2002; Schröder and Harder, 1999) within 6 days and chemotactic factors for neutrophils (such as CXCL5 and CXCL8) (Albanesi et al., 2018; Table 2) and neutrophilic infiltration (as determined by MPO staining) within 2–3 weeks of treatment in human psoriatic skin (Figure 2).

Surprisingly, there were no significant changes in overall T cell numbers including CD4+ and CD8+ T cells, as well as FoxP3 positivity indicative for regulatory T cells in the skin in the early phase (within 6 days) during dithranol treatment. Reflecting dithranol’s primary effect on the epidermal compartment, the reduction of T cell numbers in the epidermis preceded that in the dermis. Whereas dithranol had decreased T cell counts in the epidermis at week 2–3, an effect on T cell numbers in the dermis was only evident at the follow-up visit, 4–6 weeks after the end of dithranol treatment (Figure 2), in agreement with previous reports favoring dithranol’s effect on keratinocytes (Holstein et al., 2017; Swinkels et al., 2002a; Vleuten et al., 1996; Yamamoto and Nishioka, 2003).

Vleuten et al., 1996 and Swinkels et al., 2002a applied immunohistochemistry to analyze differentiation and proliferation markers as well as T cell numbers in the skin and observed, as we did, a decrease in keratin 16, restoration of filaggrin and a decrease of Ki67 in the epidermis after 2 weeks of dithranol treatment. However, their data on the effect of dithranol on dermal T cell numbers at 4 weeks was controversial (Swinkels et al., 2002a; Vleuten et al., 1996). The group of Eberle recently tested the effects of dithranol using primary keratinocytes, a 3D psoriasis tissue model and some biopsy samples from psoriasis patients and reported on a reduction in Ki67 and keratin 16 positive cells in the epidermis using immunostaining and an inhibition of the antimicrobial peptide DEFB4 using qPCR analysis. However, based on their observations, they concluded that dithranol’s anti-psoriatic effects cannot be explained by direct effects on keratinocyte differentiation or cytokine expression (Holstein et al., 2017).

Our genome-wide expression analysis indicates that dithranol primarily targets keratinocytes and that this is crucial for response to treatment, considering that differentially regulated genes in histological responders compared to non-responders belonged to pathways like keratinocyte differentiation, cornification and keratin filament formation (Supplementary file 3). The importance of dithranol’s direct effect on keratinocytes has been further substantiated by our findings generated using the mouse-tail model, a simple in vivo model to analyze effects of topical preparations on keratinocyte differentiation and parakeratosis (Bosman et al., 1992; Sebök et al., 2000; Wu et al., 2015). Similar to previous studies (Bosman et al., 1992; Hofbauer et al., 1988; Sebök et al., 2000; Wrench and Britten, 1975), we observed a strong increase in orthokeratosis after dithranol application in the mouse-tail test, reflecting its keratinocyte differentiation-inducing activity (Figure 3—figure supplement 1). Our transcriptional analysis indicated that the effect of dithranol in the mouse-tail test was linked to a strong upregulation of keratinocyte differentiation markers and several AMPs, while the pro-psoriatic antimicrobial peptide Camp/LL37 was downregulated, as well as Cxcl5, a chemotactic factor for neutrophils (Figure 3—figure supplement 2), but not other pro-psoriatic AMPs (Fritz et al., 2017; Wang et al., 2018) such as Defb3, S100a8 or S100a9. Although the mouse-tail test has evidently limitations since the disturbed cell differentiation of this model only reflects one of many aspects of psoriasis, it supports the primary effect of dithranol on keratinocytes with induced induction of orthokeratosis.

In contrast to its therapeutic effect in both keratinocyte-driven psoriasis models, the c-Jun/JunB model and mouse-tail test, dithranol did aggravate psoriatic lesions in the imiquimod model that has been solely shown to be immunologically mediated and dependent on the IL-17/IL-23 axis (van der Fits et al., 2009). In the latter model, biologics such as etanercept and anti-IL-17a agents (Liu et al., 2018), topical steroids (Sun et al., 2014) and vitamin d3 analogues (Germán et al., 2019) but also UVB and PUVA (Shirsath et al., 2018) were shown to have a beneficial effect. In contrast, dithranol significantly enhanced overall macroscopic skin thickness, consistent with a slight increase in epidermal hyperplasia and worsened inflammation (as measured by the density of cellular infiltrate in the dermis) (Figure 3—figure supplement 3). Dithranol treatment of healthy murine skin led to similar effects upon irritation, as it increased epidermal thickness and cellular infiltrate of the skin (data not shown). However, the irritant effect of dithranol may remain without functional anti-psoriatic relevance in human psoriasis (as indicated by the clinical results depicted in Figure 1—figure supplement 2 and discussed below) but might be crucial in the agent's therapeutic action in alopecia areata (Nasimi et al., 2019; Ngwanya et al., 2017).

Together, these data unambiguously demonstrate that dithranol directly acts on keratinocytes, their crosstalk with neutrophils and IL-36 signaling, with AMPs being the potential link (Figure 5). This goes also in line with the observation that Langerhans cells as another type of immune cells showed a delayed response to dithranol, with no changes during treatment and an evident increase in numbers only later on (at the follow-up visit 4–6 weeks after end of treatment). These results are consistent with previous studies performed by Swinkels et al., showing that there was no significant change in T cells or Langerhans cells during twelve days of dithranol treatment (Swinkels et al., 2002a).

Figure 5

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Our findings on dithranol’s effect on members of the IL-1 family, being beneficial for its anti-psoriatic efficacy, are well in line with recent work on blockade of IL-36 pathway as a novel strategy for the treatment of pustular psoriasis (Bachelez et al., 2019) as well as plaque-type psoriasis (Benezeder and Wolf, 2019; Mahil et al., 2017). Notably, human keratinocytes express IL-1 family members (IL-36α, IL-36β, IL-36γ, IL-36Ra) and their receptor IL-36R (D'Erme et al., 2015; Foster et al., 2014; Johnston et al., 2017). Furthermore, normal human keratinocytes show increased expression of IL-1 group mRNA after treatment with psoriasis-associated cytokines (TNFα, IL-1α, IL-17,IL-22) (Johnston et al., 2011). Genome-wide association studies revealed that deficiency in interleukin-36 receptor antagonist due to IL36RN mutations was associated with generalized pustular psoriasis (GPP) (Marrakchi et al., 2011; Sugiura et al., 2013). Supporting this notion, blocking IL-36 receptor was effective in reducing epidermal hyperplasia and showed comparable effects to etanercept in a psoriatic skin xenotransplantation model (Blumberg et al., 2010). Furthermore, successful treatment of psoriasis with the anti-psoriatic standard treatment etanercept is accompanied by a decrease in IL36A, IL36G and IL36RN expression (Johnston et al., 2011). A recent clinical phase one study provided proof-of-concept for the efficacy of BI 655130, a monoclonal antibody against the interleukin-36 receptor in the treatment of generalized pustular psoriasis (Bachelez et al., 2019). Intriguingly, topical short-contact dithranol therapy is efficacious not only in plaque-type psoriasis, but under certain conditions (i.e. after stabilization of disease activity with bland emollients) reportedly also in pustular psoriasis (Farber and Nall, 1993; Gerritsen, 1999). In this neutrophilic-driven condition, in which one might expect that dithranol worsens a heavy inflammatory state, it may have beneficial capacity by targeting the IL-36 pathway and neutrophils, both playing a most crucial role in this type of psoriasis (Bachelez, 2018; Bachelez et al., 2019; Johnston et al., 2017; Marrakchi et al., 2011; Sugiura et al., 2013).

As outlined above, we observed a strong effect of dithranol on keratinocyte-neutrophil crosstalk. Importantly, early response to anti-IL-17a blockade, as one of the most effective biological treatments currently available, has been linked to inhibition of keratinocyte-neutrophil crosstalk (Reich et al., 2015). Similar to our observation, anti-IL-17a treatment with secukinumab significantly reduced epidermal hyperproliferation after 2 weeks, decreased mRNA expression of keratinocyte-derived chemotactic factors and led to a strong decrease in IL-17a positive neutrophils. Apparently, disrupting the crosstalk between keratinocytes and neutrophils may be a crucial early effect in the clinical efficacy of secukinumab in psoriasis (Reich et al., 2015). In addition, decreased expression of AMPs like ß-defensin and S100 proteins was observed after only 1 week of anti-IL-17a treatment with secukinumab (Krueger et al., 2019) and after 2 weeks of ixekizumab treatment (Krueger et al., 2012), well in line with our observed early effect of dithranol on AMPs. Krueger et al. concluded that clinical efficacy of anti-IL-17a treatment is closely linked to early inhibition of keratinocyte-derived products such as chemokines and AMPs. Together this suggests that dithranol’s direct action on keratinocytes at the molecular level may disrupt IL-17 pathway dysregulation (without directly blocking IL-17 or its receptor), leading in turn to similar downstream effects as treatment with anti-IL-17 antagonists.

Our study also negates the paradigm that dithranol-induced irritation is crucial for its anti-psoriatic action (Gerritsen, 1999; Kucharekova et al., 2005; Prins et al., 1998; van de Kerkhof, 1991; Wiegrebe and Müller, 1995). As depicted in Figure 1—figure supplement 2, there was no correlation between dithranol-induced perilesional as well as lesional erythema and its anti-psoriatic effect, indicating that dithranol’s irritation (Prins et al., 1998; Swinkels et al., 2002c; Swinkels et al., 2002b) is a treatment side-effect unrelated to its therapeutic mechanism. However, this irritant effect of dithranol may be crucial for its action in alopecia areata, a condition, in which it was shown to be greatly effective, leading to hair regrowth in a high percentage of cases (Ngwanya et al., 2017). Similar to other topical treatment options (Nasimi et al., 2019; Yoshimasu and Furukawa, 2016), an initial irritant reaction to dithranol is followed by regrowth of hair within weeks after treatment.

What our work does not answer, is how dithranol exactly acts at the molecular level. Cell culture studies have shown that dithranol targets mitochondria (McGill et al., 2005), alters cellular metabolism (Hollywood et al., 2015) and induces apoptosis in keratinocytes (George et al., 2013; McGill et al., 2005). Dithranol also inhibits human monocytes in vitro, inhibiting secretion of IL-6, IL-8 and TNFα (Mrowietz et al., 1992; Mrowietz et al., 1997). Its effects on neutrophils were also shown in vitro, where dithranol leads to an increase in superoxide generation and a decrease in leukotriene production in neutrophils (Kavanagh et al., 1996; Schröder, 1986). Moreover, the potential receptor of dithranol remains undefined. Anti-psoriatic effects of other topical treatment options have recently been linked to modulation of the aryl hydrocarbon receptor (AhR) (Smith et al., 2017) and AhR may play a role in pathogenesis of psoriasis (Di Meglio et al., 2014). However, it appears that dithranol does not act via modulation of AhR, as we did not observe differences in the response of skin to dithranol comparing AhR knockout mice to controls (data not shown). There is need for further studies investigating how dithranol exactly acts on the molecular level, which receptor it potentially binds to or inhibits or whether it acts through modulation of a specific transcription factor such as NF-kB or STATs. Another question is whether the effect of dithranol is specific compared to other topical treatments such as steroids and vitamin D3 analogues. There seem to be some overlapping mechanisms between dithranol and vitamin D3 analogues such as calcipotriol that has been shown to act on keratinocytes to repress the expression of IL-36α/γ, an effect mediated through keratinocytic vitamin D receptor (Germán et al., 2019). Moreover, similar to dithranol, calcipotriol decreased expression of AMPs such as ß-defensins in keratinocytes of psoriatic plaques (Peric et al., 2009). At the same time, calcipotriol normalized the proinflammatory cytokine milieu and decreased IL-17A, IL-17F and IL-8 transcript abundance in lesional psoriatic skin. Calcipotriol also directly targets Th17 cells (Fujiyama et al., 2016) and CD8+IL-17+ cells (Dyring-Andersen et al., 2015), whereas we found that dithranol only has delayed effects on T cells. Moreover, cathelicidin (LL37) expression was increased by calcipotriol (Peric et al., 2009), juxtaposing the results of dithranol treatment at least in the mouse-tail test of present study. That dithranol and vitamin D3 analogues may have similar basic mechanisms of action is also supported by the notion that depending on the concentration, both dithranol (Nasimi et al., 2019; Ngwanya et al., 2017) and calcipotriol (El Taieb et al., 2019; Fullerton et al., 1998; Molinelli et al., 2020) can be irritant to the skin and induce hair regrowth in alopecia areata. Compared to vitamin D3 analogues topical steroids have an even broader mechanisms of action in psoriasis linked to their anti-inflammatory, antiproliferative, vasoconstrictive (Uva et al., 2012) and immunomodulatory properties, in particular suppressing the IL-23/IL-17 axis, with IL-23 produced by dendritic cells/macrophages and IL-17 produced by Th17 cells/γδ T cells/innate lymphoid cells (Germán et al., 2019).

Another question that this study does not answer is, whether topical dithranol therapy has any effects on systemic psoriatic inflammation. However nowadays, treatment with dithranol is mainly administered in refractory, circumscribed psoriatic lesions in patients who do not have significant systemic inflammation how it may be otherwise the case in patients with moderate to severe forms of psoriasis.

Together our work opens up several avenues for novel topical (and potentially also systemic) treatment strategies in psoriasis. Not only targeting the IL-36 pathway, but also keratinocyte differentiation regulators (e.g. involucrin), keratinocyte-produced AMPs (ß-defensins like DEFB4A, DEFB4B, DEFB103A, S100 proteins like S100A7, S100A12), and neutrophils and their chemotactic factors (CXCL5 and CXCL8) or members of the serpin family (SERPINB7 and SERPINB13), are promising approaches. Such approaches may not only be helpful for chronic plaque-psoriasis, but also for pustular psoriasis, in which a vicious loop between AMPs such as cathelicidin (LL-37) and IL-36 signaling may drive psoriatic disease (Benezeder and Wolf, 2019; Furue et al., 2018; Li et al., 2014; Madonna et al., 2019; Ngo et al., 2018).

All microarray data has been deposited at the public repository Gene Expression Omnibus (GEO) (http://www.ncbi.nlm.nih.gov/geo/) with accession numbers GSE145126 and GSE145127.

1. 1. Benezeder T
   2. Painsi C
   3. Patra V
   4. Dey S
   5. Holcmann M
   6. Lange-Asschenfeldt B
   7. Sibilia M
   8. Wolf P

   (2020) NCBI Gene Expression Omnibus

   ID GSE145126. Microarray analysis of c-Jun/JunB knockout mice treated with dithranol.

   https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE145126
2. 1. Benezeder T
   2. Painsi C
   3. Patra V
   4. Dey S
   5. Holcmann M
   6. Lange-Asschenfeldt B
   7. Sibilia M
   8. Wolf P

   (2020) NCBI Gene Expression Omnibus

   ID GSE145127. Microarray analysis of dithranol-treated psoriasis.

   https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE145127

1. 1. Albanesi C
   2. Madonna S
   3. Gisondi P
   4. Girolomoni G

   (2018) The interplay between keratinocytes and immune cells in the pathogenesis of psoriasis

   Frontiers in Immunology 9:1549.

   https://doi.org/10.3389/fimmu.2018.01549

   • PubMed
   • Google Scholar
2. 1. Bachelez H

   (2018) Pustular psoriasis and related pustular skin diseases

   British Journal of Dermatology 178:614–618.

   https://doi.org/10.1111/bjd.16232

   • PubMed
   • Google Scholar
3. 1. Bachelez H
   2. Choon SE
   3. Marrakchi S
   4. Burden AD
   5. Tsai TF
   6. Morita A
   7. Turki H
   8. Hall DB
   9. Shear M
   10. Baum P
   11. Padula SJ
   12. Thoma C

   (2019) Inhibition of the Interleukin-36 pathway for the treatment of generalized pustular psoriasis

   New England Journal of Medicine 380:981–983.

   https://doi.org/10.1056/NEJMc1811317

   • PubMed
   • Google Scholar
4. 1. Benezeder T
   2. Wolf P

   (2019) Resolution of plaque-type psoriasis: what is left behind (and reinitiates the disease)

   Seminars in Immunopathology 41:633–644.

   https://doi.org/10.1007/s00281-019-00766-z

   • PubMed
   • Google Scholar
5. 1. Bergboer JG
   2. Tjabringa GS
   3. Kamsteeg M
   4. van Vlijmen-Willems IM
   5. Rodijk-Olthuis D
   6. Jansen PA
   7. Thuret JY
   8. Narita M
   9. Ishida-Yamamoto A
   10. Zeeuwen PL
   11. Schalkwijk J

   (2011) Psoriasis risk genes of the late cornified envelope-3 group are distinctly expressed compared with genes of other LCE groups

   The American Journal of Pathology 178:1470–1477.

   https://doi.org/10.1016/j.ajpath.2010.12.017

   • PubMed
   • Google Scholar
6. 1. Bindea G
   2. Mlecnik B
   3. Hackl H
   4. Charoentong P
   5. Tosolini M
   6. Kirilovsky A
   7. Fridman WH
   8. Pagès F
   9. Trajanoski Z
   10. Galon J

   (2009) ClueGO: a cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks

   Bioinformatics 25:1091–1093.

   https://doi.org/10.1093/bioinformatics/btp101

   • PubMed
   • Google Scholar
7. 1. Blauvelt A
   2. Papp KA
   3. Griffiths CE
   4. Randazzo B
   5. Wasfi Y
   6. Shen YK
   7. Li S
   8. Kimball AB

   (2017) Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: results from the phase III, double-blinded, placebo- and active comparator-controlled VOYAGE 1 trial

   Journal of the American Academy of Dermatology 76:405–417.

   https://doi.org/10.1016/j.jaad.2016.11.041

   • PubMed
   • Google Scholar
8. 1. Blumberg H
   2. Dinh H
   3. Dean C
   4. Trueblood ES
   5. Bailey K
   6. Shows D
   7. Bhagavathula N
   8. Aslam MN
   9. Varani J
   10. Towne JE
   11. Sims JE

   (2010) IL-1RL2 and its ligands contribute to the cytokine network in psoriasis

   The Journal of Immunology 185:4354–4362.

   https://doi.org/10.4049/jimmunol.1000313

   • PubMed
   • Google Scholar
9. 1. Bosman B
   2. Matthiesen T
   3. Hess V
   4. Friderichs E

   (1992) A quantitative method for measuring antipsoriatic activity of drugs by the mouse tail test

   Skin Pharmacology and Physiology 5:41–48.

   https://doi.org/10.1159/000211016

   • Google Scholar
10. 1. D'Erme AM
    2. Wilsmann-Theis D
    3. Wagenpfeil J
    4. Hölzel M
    5. Ferring-Schmitt S
    6. Sternberg S
    7. Wittmann M
    8. Peters B
    9. Bosio A
    10. Bieber T
    11. Wenzel J

    (2015) IL-36γ (IL-1F9) is a biomarker for psoriasis skin lesions

    Journal of Investigative Dermatology 135:1025–1032.

    https://doi.org/10.1038/jid.2014.532

    • PubMed
    • Google Scholar
11. 1. de Korte J
    2. van der Valk PG
    3. Sprangers MA
    4. Damstra RJ
    5. Kunkeler AC
    6. Lijnen RL
    7. Oranje AP
    8. de Rie MA
    9. de Waard-van der Spek FB
    10. Hol CW
    11. van de Kerkhof PC

    (2008) A comparison of twice-daily calcipotriol ointment with once-daily short-contact dithranol cream therapy: quality-of-life outcomes of a randomized controlled trial of supervised treatment of psoriasis in a day-care setting

    British Journal of Dermatology 158:375–381.

    https://doi.org/10.1111/j.1365-2133.2007.08337.x

    • PubMed
    • Google Scholar
12. 1. Di Meglio P
    2. Duarte JH
    3. Ahlfors H
    4. Owens ND
    5. Li Y
    6. Villanova F
    7. Tosi I
    8. Hirota K
    9. Nestle FO
    10. Mrowietz U
    11. Gilchrist MJ
    12. Stockinger B

    (2014) Activation of the aryl hydrocarbon receptor dampens the severity of inflammatory skin conditions

    Immunity 40:989–1001.

    https://doi.org/10.1016/j.immuni.2014.04.019

    • PubMed
    • Google Scholar
13. 1. Dyring-Andersen B
    2. Bonefeld CM
    3. Bzorek M
    4. Løvendorf MB
    5. Lauritsen JP
    6. Skov L
    7. Geisler C

    (2015) The vitamin D analogue calcipotriol reduces the frequency of CD8⁺ IL-17⁺ T cells in psoriasis lesions

    Scandinavian Journal of Immunology 82:84–91.

    https://doi.org/10.1111/sji.12304

    • PubMed
    • Google Scholar
14. 1. El Taieb MA
    2. Hegazy EM
    3. Ibrahim HM
    4. Osman AB
    5. Abualhamd M

    (2019) Topical calcipotriol vs narrowband ultraviolet B in treatment of Alopecia Areata: a randomized-controlled trial

    Archives of Dermatological Research 311:629–636.

    https://doi.org/10.1007/s00403-019-01943-8

    • PubMed
    • Google Scholar
15. 1. Farber EM
    2. Nall L

    (1993) Pustular psoriasis

    Cutis 51:29–32.

    https://doi.org/10.2147/PTT.S98954

    • PubMed
    • Google Scholar
16. 1. Foster AM
    2. Baliwag J
    3. Chen CS
    4. Guzman AM
    5. Stoll SW
    6. Gudjonsson JE
    7. Ward NL
    8. Johnston A

    (2014) IL-36 promotes myeloid cell infiltration, activation, and inflammatory activity in skin

    The Journal of Immunology 192:6053–6061.

    https://doi.org/10.4049/jimmunol.1301481

    • PubMed
    • Google Scholar
17. 1. Fritz Y
    2. Klenotic PA
    3. Swindell WR
    4. Yin ZQ
    5. Groft SG
    6. Zhang L
    7. Baliwag J
    8. Camhi MI
    9. Diaconu D
    10. Young AB
    11. Foster AM
    12. Johnston A
    13. Gudjonsson JE
    14. McCormick TS
    15. Ward NL

    (2017) Induction of alternative proinflammatory cytokines accounts for sustained psoriasiform skin inflammation in IL-17C+IL-6KO mice

    Journal of Investigative Dermatology 137:696–705.

    https://doi.org/10.1016/j.jid.2016.10.021

    • Google Scholar
18. 1. Fujiyama T
    2. Ito T
    3. Umayahara T
    4. Ikeya S
    5. Tatsuno K
    6. Funakoshi A
    7. Hashizume H
    8. Tokura Y

    (2016) Topical application of a vitamin D3 analogue and corticosteroid to psoriasis plaques decreases skin infiltration of TH17 cells and their ex vivo expansion

    Journal of Allergy and Clinical Immunology 138:517–528.

    https://doi.org/10.1016/j.jaci.2016.03.048

    • PubMed
    • Google Scholar
19. 1. Fullerton A
    2. Benfeldt E
    3. Petersen JR
    4. Jensen SB
    5. Serup J

    (1998) The calcipotriol dose-irritation relationship: 48 hour occlusive testing in healthy volunteers using finn chambers

    British Journal of Dermatology 138:259–265.

    https://doi.org/10.1046/j.1365-2133.1998.02071.x

    • PubMed
    • Google Scholar
20. 1. Furue K
    2. Yamamura K
    3. Tsuji G
    4. Mitoma C
    5. Uchi H
    6. Nakahara T
    7. Kido-Nakahara M
    8. Kadono T
    9. Furue M

    (2018) Highlighting Interleukin-36 signalling in plaque psoriasis and pustular psoriasis

    Acta Dermato Venereologica 98:5–13.

    https://doi.org/10.2340/00015555-2808

    • PubMed
    • Google Scholar
21. 1. George SE
    2. Anderson RJ
    3. Haswell M
    4. Groundwater PW

    (2013) An investigation of the effects of dithranol-induced apoptosis in a human keratinocyte cell line

    Journal of Pharmacy and Pharmacology 65:552–560.

    https://doi.org/10.1111/jphp.12019

    • PubMed
    • Google Scholar
22. 1. Germán B
    2. Wei R
    3. Hener P
    4. Martins C
    5. Ye T
    6. Gottwick C
    7. Yang J
    8. Seneschal J
    9. Boniface K
    10. Li M

    (2019) Disrupting the IL-36 and IL-23/IL-17 loop underlies the efficacy of calcipotriol and corticosteroid therapy for psoriasis

    JCI Insight 4:1–17.

    https://doi.org/10.1172/jci.insight.123390

    • Google Scholar
23. Book

    1. Gerritsen MJP

    (1999)

    Dithranol

    In: van de Kerkhof PCM, editors. Textbook of Psoriasis. Blackwell Science. pp. 160–178.

    • Google Scholar
24. 1. Glitzner E
    2. Korosec A
    3. Brunner PM
    4. Drobits B
    5. Amberg N
    6. Schonthaler HB
    7. Kopp T
    8. Wagner EF
    9. Stingl G
    10. Holcmann M
    11. Sibilia M

    (2014) Specific roles for dendritic cell subsets during initiation and progression of psoriasis

    EMBO Molecular Medicine 6:1312–1327.

    https://doi.org/10.15252/emmm.201404114

    • PubMed
    • Google Scholar
25. 1. Heberle H
    2. Meirelles GV
    3. da Silva FR
    4. Telles GP
    5. Minghim R

    (2015) InteractiVenn: a web-based tool for the analysis of sets through venn diagrams

    BMC Bioinformatics 16:1–7.

    https://doi.org/10.1186/s12859-015-0611-3

    • PubMed
    • Google Scholar
26. 1. Henry J
    2. Hsu CY
    3. Haftek M
    4. Nachat R
    5. de Koning HD
    6. Gardinal-Galera I
    7. Hitomi K
    8. Balica S
    9. Jean-Decoster C
    10. Schmitt AM
    11. Paul C
    12. Serre G
    13. Simon M

    (2011) Hornerin is a component of the epidermal cornified cell envelopes

    The FASEB Journal 25:1567–1576.

    https://doi.org/10.1096/fj.10-168658

    • PubMed
    • Google Scholar
27. 1. Henry J

    (2012) Update on the epidermal differentiation complex

    Frontiers in Bioscience 17:1517–1532.

    https://doi.org/10.2741/4001

    • Google Scholar
28. 1. Hofbauer M
    2. Dowd PM
    3. Atkinson J
    4. Whitefield M
    5. Greaves MW

    (1988) Evaluation of a therapeutic concentration of dithranol in the mouse-tail test

    British Journal of Dermatology 118:85–89.

    https://doi.org/10.1111/j.1365-2133.1988.tb01754.x

    • PubMed
    • Google Scholar
29. 1. Hollywood KA
    2. Winder CL
    3. Dunn WB
    4. Xu Y
    5. Broadhurst D
    6. Griffiths CE
    7. Goodacre R

    (2015) Exploring the mode of action of dithranol therapy for psoriasis: a metabolomic analysis using HaCaT cells

    Molecular BioSystems 11:2198–2209.

    https://doi.org/10.1039/C4MB00739E

    • PubMed
    • Google Scholar
30. 1. Holstein J
    2. Fehrenbacher B
    3. Brück J
    4. Müller-Hermelink E
    5. Schäfer I
    6. Carevic M
    7. Schittek B
    8. Schaller M
    9. Ghoreschi K
    10. Eberle FC

    (2017) Anthralin modulates the expression pattern of cytokeratins and antimicrobial peptides by psoriatic keratinocytes

    Journal of Dermatological Science 87:236–245.

    https://doi.org/10.1016/j.jdermsci.2017.06.007

    • PubMed
    • Google Scholar
31. 1. Johnston A
    2. Xing X
    3. Guzman AM
    4. Riblett M
    5. Loyd CM
    6. Ward NL
    7. Wohn C
    8. Prens EP
    9. Wang F
    10. Maier LE
    11. Kang S
    12. Voorhees JJ
    13. Elder JT
    14. Gudjonsson JE

    (2011) IL-1F5, -F6, -F8, and -F9: a novel IL-1 family signaling system that is active in psoriasis and promotes keratinocyte antimicrobial peptide expression

    The Journal of Immunology 186:2613–2622.

    https://doi.org/10.4049/jimmunol.1003162

    • Google Scholar
32. 1. Johnston A
    2. Xing X
    3. Wolterink L
    4. Barnes DH
    5. Yin Z
    6. Reingold L
    7. Kahlenberg JM
    8. Harms PW
    9. Gudjonsson JE

    (2017) IL-1 and IL-36 are dominant cytokines in generalized pustular psoriasis

    Journal of Allergy and Clinical Immunology 140:109–120.

    https://doi.org/10.1016/j.jaci.2016.08.056

    • PubMed
    • Google Scholar
33. 1. Kavanagh GM
    2. Burton JL
    3. Donnell VO

    (1996) Effects of dithranol on neutrophil superoxide generation in patients with psoriasis

    British Journal of Dermatology 134:234–237.

    https://doi.org/10.1111/j.1365-2133.1996.tb07607.x

    • PubMed
    • Google Scholar
34. 1. Kemény L
    2. Ruzicka T
    3. Braun-Falco O

    (1990) Dithranol: a review of the mechanism of action in the treatment of psoriasis vulgaris

    Skin Pharmacology and Physiology 3:1–20.

    https://doi.org/10.1159/000210836

    • Google Scholar
35. 1. Krueger G
    2. Koo J
    3. Lebwohl M
    4. Menter A
    5. Stern RS
    6. Rolstad T

    (2001)

    The impact of psoriasis on quality of life: results of a 1998 national psoriasis foundation patient-membership survey

    Archives of Dermatology 137:280–284.

    • PubMed
    • Google Scholar
36. 1. Krueger JG
    2. Fretzin S
    3. Suárez-Fariñas M
    4. Haslett PA
    5. Phipps KM
    6. Cameron GS
    7. McColm J
    8. Katcherian A
    9. Cueto I
    10. White T
    11. Banerjee S
    12. Hoffman RW

    (2012) IL-17A is essential for cell activation and inflammatory gene circuits in subjects with psoriasis

    Journal of Allergy and Clinical Immunology 130:145–154.

    https://doi.org/10.1016/j.jaci.2012.04.024

    • PubMed
    • Google Scholar
37. 1. Krueger JG
    2. Wharton KA
    3. Schlitt T
    4. Suprun M
    5. Torene RI
    6. Jiang X
    7. Wang CQ
    8. Fuentes-Duculan J
    9. Hartmann N
    10. Peters T
    11. Koroleva I
    12. Hillenbrand R
    13. Letzkus M
    14. Yu X
    15. Li Y
    16. Glueck A
    17. Hasselberg A
    18. Flannery B
    19. Suárez-Fariñas M
    20. Hueber W

    (2019) IL-17A inhibition by secukinumab induces early clinical, Histopathologic, and molecular resolution of psoriasis

    Journal of Allergy and Clinical Immunology 144:750–763.

    https://doi.org/10.1016/j.jaci.2019.04.029

    • PubMed
    • Google Scholar
38. 1. Kucharekova M
    2. Lieffers L
    3. van de Kerkhof PC
    4. van der Valk PG

    (2005) Dithranol irritation in psoriasis treatment: a study of 68 inpatients

    Journal of the European Academy of Dermatology and Venereology 19:176–179.

    https://doi.org/10.1111/j.1468-3083.2005.01093.x

    • PubMed
    • Google Scholar
39. Book

    1. Kucharekova M
    2. Van De Kerkhof PCM
    3. Schalkwijk J
    4. Van Der Valk PGM

    (2006) Dithranol

    In: Chew AL, Maibach HI, editors. Irritant Dermatitis. Springer. pp. 317–322.

    https://doi.org/10.1007/3-540-31294-3_34

    • Google Scholar
40. 1. Kuechle MK
    2. Predd HM
    3. Fleckman P
    4. Dale BA
    5. Presland RB

    (2001) Caspase-14, a keratinocyte specific caspase: mrna splice variants and expression pattern in embryonic and adult mouse

    Cell Death & Differentiation 8:868–870.

    https://doi.org/10.1038/sj.cdd.4400897

    • Google Scholar
41. 1. Langley RG
    2. Gupta A
    3. Papp K
    4. Wexler D
    5. Østerdal ML
    6. Curčić D

    (2011) Calcipotriol plus betamethasone dipropionate gel compared with tacalcitol ointment and the gel vehicle alone in patients with psoriasis vulgaris: a randomized, controlled clinical trial

    Dermatology 222:148–156.

    https://doi.org/10.1159/000323408

    • PubMed
    • Google Scholar
42. 1. Langley RG
    2. Elewski BE
    3. Lebwohl M
    4. Reich K
    5. Griffiths CE
    6. Papp K
    7. Puig L
    8. Nakagawa H
    9. Spelman L
    10. Sigurgeirsson B
    11. Rivas E
    12. Tsai TF
    13. Wasel N
    14. Tyring S
    15. Salko T
    16. Hampele I
    17. Notter M
    18. Karpov A
    19. Helou S
    20. Papavassilis C
    21. ERASURE Study Group
    22. FIXTURE Study Group

    (2014) Secukinumab in plaque psoriasis--results of two phase 3 trials

    New England Journal of Medicine 371:326–338.

    https://doi.org/10.1056/NEJMoa1314258

    • PubMed
    • Google Scholar
43. 1. Li N
    2. Yamasaki K
    3. Saito R
    4. Fukushi-Takahashi S
    5. Shimada-Omori R
    6. Asano M
    7. Aiba S

    (2014) Alarmin function of cathelicidin antimicrobial peptide LL37 through IL-36γ induction in human epidermal keratinocytes

    The Journal of Immunology 193:5140–5148.

    https://doi.org/10.4049/jimmunol.1302574

    • PubMed
    • Google Scholar
44. 1. Liu AY
    2. Destoumieux D
    3. Wong AV
    4. Park CH
    5. Valore EV
    6. Liu L
    7. Ganz T

    (2002) Human beta-defensin-2 production in keratinocytes is regulated by interleukin-1, Bacteria, and the state of differentiation

    Journal of Investigative Dermatology 118:275–281.

    https://doi.org/10.1046/j.0022-202x.2001.01651.x

    • PubMed
    • Google Scholar
45. 1. Liu Z
    2. Liu H
    3. Xu P
    4. Yin Q
    5. Wang Y
    6. Opoku YK
    7. Yang J
    8. Song L
    9. Sun X
    10. Zhang T
    11. Yu D
    12. Wang X
    13. Ren G
    14. Li D

    (2018) Ameliorative effects of a fusion protein dual targeting interleukin 17A and tumor necrosis factor α on imiquimod-induced psoriasis in mice

    Biomedicine & Pharmacotherapy 108:1425–1434.

    https://doi.org/10.1016/j.biopha.2018.09.178

    • Google Scholar
46. 1. Madonna S
    2. Girolomoni G
    3. Dinarello CA
    4. Albanesi C

    (2019) The significance of IL-36 hyperactivation and IL-36R targeting in psoriasis

    International Journal of Molecular Sciences 20:1–14.

    https://doi.org/10.3390/ijms20133318

    • Google Scholar
47. 1. Mahil SK
    2. Catapano M
    3. Di Meglio P
    4. Dand N
    5. Ahlfors H
    6. Carr IM
    7. Smith CH
    8. Trembath RC
    9. Peakman M
    10. Wright J
    11. Ciccarelli FD
    12. Barker JN
    13. Capon F

    (2017) An analysis of IL-36 signature genes and individuals with IL1RL2 knockout mutations validates IL-36 as a psoriasis therapeutic target

    Science Translational Medicine 9:eaan2514.

    https://doi.org/10.1126/scitranslmed.aan2514

    • PubMed
    • Google Scholar
48. 1. Marrakchi S
    2. Guigue P
    3. Renshaw BR
    4. Puel A
    5. Pei XY
    6. Fraitag S
    7. Zribi J
    8. Bal E
    9. Cluzeau C
    10. Chrabieh M
    11. Towne JE
    12. Douangpanya J
    13. Pons C
    14. Mansour S
    15. Serre V
    16. Makni H
    17. Mahfoudh N
    18. Fakhfakh F
    19. Bodemer C
    20. Feingold J
    21. Hadj-Rabia S
    22. Favre M
    23. Genin E
    24. Sahbatou M
    25. Munnich A
    26. Casanova JL
    27. Sims JE
    28. Turki H
    29. Bachelez H
    30. Smahi A

    (2011) Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis

    New England Journal of Medicine 365:620–628.

    https://doi.org/10.1056/NEJMoa1013068

    • PubMed
    • Google Scholar
49. 1. McGill A
    2. Frank A
    3. Emmett N
    4. Turnbull DM
    5. Birch-Machin MA
    6. Reynolds NJ

    (2005) The anti-psoriatic drug anthralin accumulates in keratinocyte mitochondria, dissipates mitochondrial membrane potential, and induces apoptosis through a pathway dependent on respiratory competent mitochondria

    The FASEB Journal 19:1012–1014.

    https://doi.org/10.1096/fj.04-2664fje

    • PubMed
    • Google Scholar
50. 1. Molinelli E
    2. Campanati A
    3. Brisigotti V
    4. Sapigni C
    5. Paolinelli M
    6. Offidani A

    (2020) Efficacy and safety of topical calcipotriol 0.005% Versus topical clobetasol 0.05% in the management of Alopecia Areata: an intrasubject pilot study

    Dermatology and Therapy 10:515–521.

    https://doi.org/10.1007/s13555-020-00379-7

    • PubMed
    • Google Scholar
51. 1. Mrowietz U
    2. Falsafi M
    3. Schröder JM
    4. Christophers E

    (1992) Inhibition of human monocyte functions by anthralin

    British Journal of Dermatology 127:382–386.

    https://doi.org/10.1111/j.1365-2133.1992.tb00458.x

    • PubMed
    • Google Scholar
52. 1. Mrowietz U
    2. Jessat H
    3. Schwarz A
    4. Schwarz T

    (1997) Anthralin (dithranol) in vitro inhibits human monocytes to secrete IL-6, IL-8 and TNF-alpha, but not IL-1

    British Journal of Dermatology 136:542–547.

    https://doi.org/10.1111/j.1365-2133.1997.tb02138.x

    • PubMed
    • Google Scholar
53. 1. Nasimi M
    2. Ghandi N
    3. Abedini R
    4. Mirshamsi A
    5. Shakoei S
    6. Seirafi H

    (2019) Efficacy and safety of anthralin in combination with diphenylcyclopropenone in the treatment of Alopecia Areata: a retrospective case series

    Archives of Dermatological Research 311:607–613.

    https://doi.org/10.1007/s00403-019-01940-x

    • PubMed
    • Google Scholar
54. 1. Nast A
    2. Boehncke WH
    3. Mrowietz U
    4. Ockenfels HM
    5. Philipp S
    6. Reich K
    7. Rzany B

    (2012) Guidelines on the treatment of psoriasis vulgaris

    Journal Der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG 10:1–95.

    https://doi.org/10.1111/j.1610-0387.2012.07919.x

    • Google Scholar
55. 1. Ngo VL
    2. Abo H
    3. Maxim E
    4. Harusato A
    5. Geem D
    6. Medina-Contreras O
    7. Merlin D
    8. Gewirtz AT
    9. Nusrat A
    10. Denning TL

    (2018) A cytokine network involving IL-36γ, IL-23, and IL-22 promotes antimicrobial defense and recovery from intestinal barrier damage

    PNAS 115:E5076–E5085.

    https://doi.org/10.1073/pnas.1718902115

    • PubMed
    • Google Scholar
56. 1. Ngwanya MR
    2. Gray NA
    3. Gumedze F
    4. Ndyenga A
    5. Khumalo NP

    (2017) Higher concentrations of dithranol appear to induce hair growth even in severe Alopecia Areata

    Dermatologic Therapy 30:e12500–e12505.

    https://doi.org/10.1111/dth.12500

    • Google Scholar
57. 1. Painsi C
    2. Patscheider M
    3. Inzinger M
    4. Huegel R
    5. Lange-Asschenfeldt B
    6. Quehenberger F
    7. Wolf P

    (2015a) Psoriasis area and severity index 75 rate of classical inpatient dithranol therapy under daily life conditions

    British Journal of Dermatology 173:815–817.

    https://doi.org/10.1111/bjd.13744

    • PubMed
    • Google Scholar
58. 1. Painsi C
    2. Patscheider M
    3. Inzinger M
    4. Lange-Asschenfeldt B
    5. Quehenberger F
    6. Wolf P

    (2015b) Patient perspectives on treating psoriasis with classic inpatient dithranol therapy: a retrospective patient survey

    JDDG: Journal Der Deutschen Dermatologischen Gesellschaft 13:1156–1163.

    https://doi.org/10.1111/ddg.12820

    • Google Scholar
59. 1. Papp KA
    2. Blauvelt A
    3. Bukhalo M
    4. Gooderham M
    5. Krueger JG
    6. Lacour JP
    7. Menter A
    8. Philipp S
    9. Sofen H
    10. Tyring S
    11. Berner BR
    12. Visvanathan S
    13. Pamulapati C
    14. Bennett N
    15. Flack M
    16. Scholl P
    17. Padula SJ

    (2017) Risankizumab versus Ustekinumab for Moderate-to-Severe plaque psoriasis

    New England Journal of Medicine 376:1551–1560.

    https://doi.org/10.1056/NEJMoa1607017

    • PubMed
    • Google Scholar
60. 1. Peric M
    2. Koglin S
    3. Dombrowski Y
    4. Gross K
    5. Bradac E
    6. Büchau A
    7. Steinmeyer A
    8. Zügel U
    9. Ruzicka T
    10. Schauber J

    (2009) Vitamin D analogs differentially control antimicrobial peptide/"alarmin" expression in psoriasis

    PLOS ONE 4:e6340.

    https://doi.org/10.1371/journal.pone.0006340

    • PubMed
    • Google Scholar
61. 1. Prins M
    2. Swinkels OQ
    3. Kolkman EG
    4. Wuis EW
    5. Hekster YA
    6. van der Valk PG

    (1998) Skin irritation by dithranol cream A blind study to assess the role of the cream formulation

    Acta Dermato-Venereologica 78:262–265.

    https://doi.org/10.1080/000155598441828

    • PubMed
    • Google Scholar
62. 1. Reich K
    2. Papp KA
    3. Matheson RT
    4. Tu JH
    5. Bissonnette R
    6. Bourcier M
    7. Gratton D
    8. Kunynetz RA
    9. Poulin Y
    10. Rosoph LA
    11. Stingl G
    12. Bauer WM
    13. Salter JM
    14. Falk TM
    15. Blödorn-Schlicht NA
    16. Hueber W
    17. Sommer U
    18. Schumacher MM
    19. Peters T
    20. Kriehuber E
    21. Lee DM
    22. Wieczorek GA
    23. Kolbinger F
    24. Bleul CC

    (2015) Evidence that a neutrophil-keratinocyte crosstalk is an early target of IL-17A inhibition in psoriasis

    Experimental Dermatology 24:529–535.

    https://doi.org/10.1111/exd.12710

    • Google Scholar
63. 1. Reich K
    2. Jackson K
    3. Ball S
    4. Garces S
    5. Kerr L
    6. Chua L
    7. Muram TM
    8. Blauvelt A

    (2018) Ixekizumab pharmacokinetics, Anti-Drug antibodies, and efficacy through 60 weeks of Treatment of Moderate to Severe Plaque Psoriasis

    Journal of Investigative Dermatology 138:2168–2173.

    https://doi.org/10.1016/j.jid.2018.04.019

    • PubMed
    • Google Scholar
64. 1. Roberson ED
    2. Bowcock AM

    (2010) Psoriasis genetics: breaking the barrier

    Trends in Genetics 26:415–423.

    https://doi.org/10.1016/j.tig.2010.06.006

    • PubMed
    • Google Scholar
65. 1. Sandilands A
    2. Sutherland C
    3. Irvine AD
    4. McLean WH

    (2009) Filaggrin in the frontline: role in skin barrier function and disease

    Journal of Cell Science 122:1285–1294.

    https://doi.org/10.1242/jcs.033969

    • PubMed
    • Google Scholar
66. 1. Schaarschmidt ML
    2. Kromer C
    3. Herr R
    4. Schmieder A
    5. Goerdt S
    6. Peitsch WK

    (2015) Treatment satisfaction of patients with psoriasis

    Acta Dermato Venereologica 95:572–578.

    https://doi.org/10.2340/00015555-2011

    • PubMed
    • Google Scholar
67. 1. Schonthaler HB
    2. Huggenberger R
    3. Wculek SK
    4. Detmar M
    5. Wagner EF

    (2009) Systemic anti-VEGF treatment strongly reduces skin inflammation in a mouse model of psoriasis

    PNAS 106:21264–21269.

    https://doi.org/10.1073/pnas.0907550106

    • PubMed
    • Google Scholar
68. 1. Schröder JM

    (1986) Anthralin (1,8-dihydroxyanthrone) is a potent inhibitor of leukotriene production and LTB4-omega oxidation by human neutrophils

    Journal of Investigative Dermatology 87:624–629.

    https://doi.org/10.1111/1523-1747.ep12456188

    • PubMed
    • Google Scholar
69. 1. Schröder JM
    2. Harder J

    (1999) Human beta-defensin-2

    The International Journal of Biochemistry & Cell Biology 31:645–651.

    https://doi.org/10.1016/S1357-2725(99)00013-8

    • PubMed
    • Google Scholar
70. 1. Sebök B
    2. Bonnekoh B
    3. Kerényi M
    4. Gollnick H

    (2000) Tazarotene induces epidermal cell differentiation in the mouse tail test used as an animal model for psoriasis

    Skin Pharmacology and Physiology 13:285–291.

    https://doi.org/10.1159/000029935

    • Google Scholar
71. 1. Sehgal VN
    2. Verma P
    3. Khurana A

    (2014) Anthralin/dithranol in dermatology

    International Journal of Dermatology 53:e449–e460.

    https://doi.org/10.1111/j.1365-4632.2012.05611.x

    • PubMed
    • Google Scholar
72. 1. Shannon P
    2. Markiel A
    3. Ozier O
    4. Baliga NS
    5. Wang JT
    6. Ramage D
    7. Ideker T

    (2003) Cytoscape: a software environment for integrated models

    Genome Research 13:2498–2504.

    https://doi.org/10.1101/gr.1239303

    • Google Scholar
73. 1. Shirsath N
    2. Wagner K
    3. Tangermann S
    4. Schlederer M
    5. Ringel C
    6. Kenner L
    7. Brüne B
    8. Wolf P

    (2018) 8-Methoxypsoralen plus ultraviolet A reduces the psoriatic response to imiquimod in a murine model

    Acta Dermato Venereologica 98:576–584.

    https://doi.org/10.2340/00015555-2905

    • PubMed
    • Google Scholar
74. 1. Sivaprasad U
    2. Kinker KG
    3. Ericksen MB
    4. Lindsey M
    5. Gibson AM
    6. Bass SA
    7. Hershey NS
    8. Deng J
    9. Medvedovic M
    10. Khurana Hershey GK

    (2015) SERPINB3/B4 contributes to early inflammation and barrier dysfunction in an experimental murine model of atopic dermatitis

    Journal of Investigative Dermatology 135:160–169.

    https://doi.org/10.1038/jid.2014.353

    • PubMed
    • Google Scholar
75. 1. Smith SH
    2. Jayawickreme C
    3. Rickard DJ
    4. Nicodeme E
    5. Bui T
    6. Simmons C
    7. Coquery CM
    8. Neil J
    9. Pryor WM
    10. Mayhew D
    11. Rajpal DK
    12. Creech K
    13. Furst S
    14. Lee J
    15. Wu D
    16. Rastinejad F
    17. Willson TM
    18. Viviani F
    19. Morris DC
    20. Moore JT
    21. Cote-Sierra J

    (2017) Tapinarof is a natural AhR agonist that Resolves Skin Inflammation in Mice and Humans

    Journal of Investigative Dermatology 137:2110–2119.

    https://doi.org/10.1016/j.jid.2017.05.004

    • PubMed
    • Google Scholar
76. Conference

    1. Stern RS
    2. Nijsten T
    3. Feldman SR
    4. Margolis DJ
    5. Rolstad T

    (2004) Psoriasis is common, carries a substantial burden even when not extensive, and is associated with widespread treatment dissatisfaction

    Journal of Investigative Dermatology Symposium Proceedings. pp. 136–139.

    https://doi.org/10.1046/j.1087-0024.2003.09102.x

    • Google Scholar
77. 1. Suárez-Fariñas M
    2. Li K
    3. Fuentes-Duculan J
    4. Hayden K
    5. Brodmerkel C
    6. Krueger JG

    (2012) Expanding the psoriasis disease profile: interrogation of the skin and serum of patients with moderate-to-severe psoriasis

    Journal of Investigative Dermatology 132:2552–2564.

    https://doi.org/10.1038/jid.2012.184

    • PubMed
    • Google Scholar
78. 1. Sugiura K
    2. Takemoto A
    3. Yamaguchi M
    4. Takahashi H
    5. Shoda Y
    6. Mitsuma T
    7. Tsuda K
    8. Nishida E
    9. Togawa Y
    10. Nakajima K
    11. Sakakibara A
    12. Kawachi S
    13. Shimizu M
    14. Ito Y
    15. Takeichi T
    16. Kono M
    17. Ogawa Y
    18. Muro Y
    19. Ishida-Yamamoto A
    20. Sano S
    21. Matsue H
    22. Morita A
    23. Mizutani H
    24. Iizuka H
    25. Muto M
    26. Akiyama M

    (2013) The majority of generalized pustular psoriasis without psoriasis vulgaris is caused by deficiency of interleukin-36 receptor antagonist

    Journal of Investigative Dermatology 133:2514–2521.

    https://doi.org/10.1038/jid.2013.230

    • PubMed
    • Google Scholar
79. 1. Sun J
    2. Dou W
    3. Zhao Y
    4. Hu J

    (2014) A comparison of the effects of topical treatment of calcipotriol, camptothecin, clobetasol and tazarotene on an imiquimod-induced psoriasis-like mouse model

    Immunopharmacology and Immunotoxicology 36:17–24.

    https://doi.org/10.3109/08923973.2013.862542

    • PubMed
    • Google Scholar
80. 1. Swinkels OQJ
    2. Prins M
    3. Gerritsen MJP
    4. van Vlijmen-Willems IMJJ
    5. van der Valk PGM
    6. van de Kerkhof PCM

    (2002a) An immunohistochemical assessment of the response of the psoriatic lesion to single and repeated applications of High-Dose dithranol cream

    Skin Pharmacology and Physiology 15:393–400.

    https://doi.org/10.1159/000066450

    • Google Scholar
81. 1. Swinkels OQJ
    2. Prins M
    3. van Vlijmen-Willems IMJJ
    4. Gerritsen MJP
    5. van der Valk PGM
    6. van de Kerkhof PCM

    (2002b) The response of uninvolved skin of patients with psoriasis to single and repeated applications of dithranol cream: an immunohistochemical assessment

    Skin Pharmacology and Physiology 15:385–392.

    https://doi.org/10.1159/000066449

    • Google Scholar
82. 1. Swinkels OQ
    2. Prins M
    3. Birker LW
    4. Gerritsen MJ
    5. van der Valk PG
    6. van de Kerkhof PC

    (2002c) The response of normal human skin to single and repeated applications of dithranol cream: an immunohistochemical assessment

    Skin Pharmacology and Physiology 15:262–269.

    https://doi.org/10.1159/000065972

    • PubMed
    • Google Scholar
83. 1. Swinkels OQ
    2. Prins M
    3. Veeniiuis RT
    4. De Boo T
    5. Gerritsen MJ
    6. Van Der Wilt GJ
    7. Van De Kerkhof PC
    8. Van Der Valk PG

    (2004)

    Effectiveness and side effects of UVB-phototherapy, dithranol inpatient therapy and a care instruction programme of short contact dithranol in moderate to severe psoriasis

    European Journal of Dermatology : EJD 14:159–165.

    • PubMed
    • Google Scholar
84. 1. Tian S
    2. Krueger JG
    3. Li K
    4. Jabbari A
    5. Brodmerkel C
    6. Lowes MA
    7. Suárez-Fariñas M

    (2012) Meta-analysis derived (MAD) transcriptome of psoriasis defines the "core" pathogenesis of disease

    PLOS ONE 7:e44274.

    https://doi.org/10.1371/journal.pone.0044274

    • PubMed
    • Google Scholar
85. 1. Toulza E
    2. Mattiuzzo NR
    3. Galliano MF
    4. Jonca N
    5. Dossat C
    6. Jacob D
    7. de Daruvar A
    8. Wincker P
    9. Serre G
    10. Guerrin M

    (2007) Large-scale identification of human genes implicated in epidermal barrier function

    Genome Biology 8:R107.

    https://doi.org/10.1186/gb-2007-8-6-r107

    • PubMed
    • Google Scholar
86. 1. Uva L
    2. Miguel D
    3. Pinheiro C
    4. Antunes J
    5. Cruz D
    6. Ferreira J
    7. Filipe P

    (2012) Mechanisms of action of topical corticosteroids in psoriasis

    International Journal of Endocrinology 2012:1–16.

    https://doi.org/10.1155/2012/561018

    • Google Scholar
87. 1. van de Kerkhof PCM

    (1991)

    Dithranol treatment for psoriasis: after 75 years still going strong!

    European Journal of Dermatology 1:79–88.

    • Google Scholar
88. 1. van de Kerkhof PC

    (2015) An update on topical therapies for mild-moderate psoriasis

    Dermatologic Clinics 33:73–77.

    https://doi.org/10.1016/j.det.2014.09.006

    • PubMed
    • Google Scholar
89. 1. van der Fits L
    2. Mourits S
    3. Voerman JS
    4. Kant M
    5. Boon L
    6. Laman JD
    7. Cornelissen F
    8. Mus AM
    9. Florencia E
    10. Prens EP
    11. Lubberts E

    (2009) Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 Axis

    The Journal of Immunology 182:5836–5845.

    https://doi.org/10.4049/jimmunol.0802999

    • PubMed
    • Google Scholar
90. 1. Vleuten CJM
    2. Jong EMGJ
    3. Kerkhof PCM

    (1996) Epidermal differentiation characteristics of the psoriatic plaque during short contact treatment with dithranol cream

    Clinical and Experimental Dermatology 21:409–414.

    https://doi.org/10.1111/j.1365-2230.1996.tb00143.x

    • Google Scholar
91. 1. Wang S
    2. Song R
    3. Wang Z
    4. Jing Z
    5. Wang S
    6. Ma J

    (2018) S100A8/A9 in inflammation

    Frontiers in Immunology 9:1298.

    https://doi.org/10.3389/fimmu.2018.01298

    • PubMed
    • Google Scholar
92. 1. Wiegrebe W
    2. Müller K

    (1995) Treatment of psoriasis with anthrones – Chemical Principles, Biochemical Aspects, and Approaches to the Design of Novel Derivatives

    Skin Pharmacology and Physiology 8:1–24.

    https://doi.org/10.1159/000211326

    • Google Scholar
93. 1. Wolf R
    2. Orion E
    3. Ruocco E
    4. Ruocco V

    (2012) Abnormal epidermal barrier in the pathogenesis of psoriasis

    Clinics in Dermatology 30:323–328.

    https://doi.org/10.1016/j.clindermatol.2011.08.022

    • PubMed
    • Google Scholar
94. 1. Wrench R
    2. Britten AZ

    (1975) Evaluation of coal tar fractions for use in psoriasiform diseases using the mouse tail test. (II) Tar oil acids

    British Journal of Dermatology 92:575–579.

    https://doi.org/10.1111/j.1365-2133.1975.tb03127.x

    • PubMed
    • Google Scholar
95. 1. Wu J
    2. Li H
    3. Li M

    (2015)

    Effects of baicalin cream in two mouse models: 2,4-dinitrofluorobenzene-induced contact hypersensitivity and mouse tail test for psoriasis

    International Journal of Clinical and Experimental Medicine 8:2128–2137.

    • PubMed
    • Google Scholar
96. 1. Yamamoto T
    2. Nishioka K

    (2003) Alteration of the expression of Bcl-2, Bcl-x, bax, fas, and fas ligand in the involved skin of psoriasis vulgaris following topical anthralin therapy

    Skin Pharmacology and Physiology 16:50–58.

    https://doi.org/10.1159/000068289

    • Google Scholar
97. 1. Yoshimasu T
    2. Furukawa F

    (2016) Modified immunotherapy for alopecia areata

    Autoimmunity Reviews 15:664–667.

    https://doi.org/10.1016/j.autrev.2016.02.021

    • PubMed
    • Google Scholar
98. 1. Zenz R
    2. Eferl R
    3. Kenner L
    4. Florin L
    5. Hummerich L
    6. Mehic D
    7. Scheuch H
    8. Angel P
    9. Tschachler E
    10. Wagner EF

    (2005) Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of jun proteins

    Nature 437:369–375.

    https://doi.org/10.1038/nature03963

    • PubMed
    • Google Scholar

Author details

1. Theresa Benezeder

   Department of Dermatology, Medical University of Graz, Graz, Austria

   Contribution

   Conceptualization, Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing - original draft, Project administration

   Contributed equally with

   Clemens Painsi

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-6218-2792

2. Clemens Painsi

   State Hospital Klagenfurt, Klagenfurt am Wörthersee, Austria

   Contribution

   Conceptualization, Data curation, Investigation, Project administration

   Contributed equally with

   Theresa Benezeder

   Competing interests

   No competing interests declared

3. VijayKumar Patra

   Department of Dermatology, Medical University of Graz, Graz, Austria

   Contribution

   Visualization, Methodology

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-7161-7767

4. Saptaswa Dey

   Department of Dermatology, Medical University of Graz, Graz, Austria

   Contribution

   Methodology

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-7532-7858

5. Martin Holcmann

   Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria

   Contribution

   Resources, Methodology

   Competing interests

   No competing interests declared

6. Bernhard Lange-Asschenfeldt

   State Hospital Klagenfurt, Klagenfurt am Wörthersee, Austria

   Contribution

   Resources, Project administration

   Competing interests

   No competing interests declared

7. Maria Sibilia

   Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria

   Contribution

   Resources, Writing - review and editing

   Competing interests

   No competing interests declared

8. Peter Wolf

   Department of Dermatology, Medical University of Graz, Graz, Austria

   Contribution

   Conceptualization, Supervision, Funding acquisition, Writing - review and editing

   For correspondence

   peter.wolf@medunigraz.at

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-7777-9444

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