Atopic dermatitis: an expanding therapeutic pipeline for a complex disease

S1P has been reported to be increased in various conditions, including multiple sclerosis, neurodegeneration, pneumonia, psoriasis, asthma, and more recently AD.

“S1P acts via gradients in circulatory fluids and has been reported to be increased in various conditions such as multiple sclerosis and neurodegeneration158, pneumonia159, psoriasis160, asthma161 and more recently in AD162.”

• cites [158] Alessenko, A. V. & Albi, E. Exploring sphingolipid implications in neurodegeneration. Front. Neurol. 11, 437 (2020). sourceDisputed

  Citation 158 is attached to the multiple-sclerosis and neurodegeneration portion of the sentence, not to pneumonia, psoriasis, asthma, or AD. The Alzheimer's Disease section reports reduced S1P in a brain region of patients with AD, a neurodegenerative condition, rather than increased S1P. The Neurodegenerative Disorders section says sphingolipids change in these diseases but does not establish an S1P increase in multiple sclerosis (page numbers unavailable). (LLM, conf=0.82)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured
• cites [159] Hsu, S. C. et al. Circulating sphingosine-1-phosphate as a prognostic biomarker for community-acquired pneumonia. PLoS ONE 14, e0216963 (2019). sourceSupported
• cites [160] Checa, A. et al. Circulating levels of sphingosine-1-phosphate are elevated in severe, but not mild psoriasis and are unresponsive to anti-TNF-alpha treatment. Sci. Rep. 5, 12017 (2015). sourcePartly supported

  Citation 160 is attached to psoriasis, not the other conditions listed. The Results report elevated circulating S1P in severe psoriasis compared with healthy controls, but no significant difference in mild psoriasis. The unqualified reference to psoriasis omits that limitation. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [161] Kim, S. H. et al. Ceramide/sphingosine-1-phosphate imbalance is associated with distinct inflammatory phenotypes of uncontrolled asthma. Allergy 75, 1991–2004 (2020). sourceNot checked — no full text of the source
• cites [162] Sakai, T. et al. Serum sphingosine-1-phosphate is elevated in atopic dermatitis and associated with the severity and inflammation. Allergy https://doi.org/10.1111/all.14826 (2021). sourceNot checked — no full text of the source

Disease severity remains the basis for the treatment algorithm in current atopic dermatitis guidelines.

“For practical purposes, disease severity remains the basis for the treatment algorithm in the current guidelines31–35.”

• cites [31] Wollenberg, A. et al. Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults and children: part I. J. Eur. Acad. Dermatol. Venereol. 32, 657–682 (2018). sourceNot checked — no full text of the source
• cites [32] Wollenberg, A. et al. Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults and children: part II. J. Eur. Acad. Dermatol. Venereol. 32, 850–878 (2018). sourceNot checked — no full text of the source
• cites [33] Katayama, I. et al. Japanese guidelines for atopic dermatitis 2017. Allergol. Int. 66, 230–247 (2017). sourceNot checked — no full text of the source
• cites [34] Eichenfield, L. F. et al. Current guidelines for the evaluation and management of atopic dermatitis: a comparison of the Joint Task Force Practice Parameter and American Academy of Dermatology guidelines. J. Allergy Clin. Immunol. 139, S49–S57 (2017). sourceNot checked — no full text of the source
• cites [35] Wollenberg, A. et al. ETFAD/EADV Eczema Task Force 2020 Position Paper on diagnosis and treatment of atopic dermatitis in adults and children. J. Eur. Acad. Dermatol. Venereol. 34, 2717–2744 (2020). sourceSupported
  Experimental — accuracy not yet measured

Baricitinib is a small molecule that interacts with multiple signal transduction pathways linked to several cytokine receptors and immune pathways.

“whereas baricitinib exemplifies a more wide-ranging approach using small molecules17 that interact with multiple signal transduction pathways linked to several cytokine receptors and immune pathways.”

• cites [17] Schwartz, D. M. et al. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat. Rev. Drug Discov. 16, 843–862 (2017). Excellent review on the mode of action of JAK inhibitors. sourceSupported

The sequential and/or cumulative immunological events underlying the complex clinical phenotype are key to understanding the value of targeted therapies for distinct pathways such as TH2, TH17, and/or TH22.

“The sequential and/or cumulative immunological events that underlie the complex clinical phenotype are key to understanding the value of targeted therapies for distinct pathways such as TH2, TH17 and/or TH22 response124,125.”

• cites [124] Czarnowicki, T. et al. Evolution of pathologic T-cell subsets in patients with atopic dermatitis from infancy to adulthood. J. Allergy Clin. Immunol. 145, 215–228 (2020). sourceSupported
• cites [125] Renert-Yuval, Y. et al. The molecular features of normal and atopic dermatitis skin in infants, children, adolescents and adults. J. Allergy Clin. Immunol. 148, 148–163 (2021). sourcePartly supported

  The Results describe age-related differences in TH2, TH17 and TH22 markers, and the Discussion says these differences may inform the choice of targeted treatment. The paper does not establish sequential or cumulative immunological events underlying the clinical phenotype, or the value of therapies targeting each of the three pathways; it says the treatment implications require age-specific clinical trials. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Mutations or variants of genes such as SPINK5 favour the generation of allergen-independent, nonspecific inflammation, providing a pro-TH2 micromilieu via keratinocyte-derived alarmins such as TSLP, IL-33, and IL-25.

“Mutations or variants of genes such as SPINK5 favour the generation of allergen-independent, nonspecific inflammation, providing a pro-T helper 2 (TH2) micromilieu by virtue of keratinocyte-derived alarmins such as thymic stromal lymphopoietin (TSLP), IL-33 and IL-25 (refs52,64).”

• cites [52] Briot, A. et al. Kallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome. J. Exp. Med. 206, 1135–1147 (2009). sourcePartly supported

  The Discussion (Figure 8; page unavailable) describes SPINK5 deficiency as initiating inflammation independently of environmental factors and creating a pro-Th2 microenvironment through keratinocyte-derived TSLP. The cited paper does not identify IL-33 or IL-25 as mediators of that pathway, so it supports only part of the attributed claim. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [64] Hammad, H. & Lambrecht, B. N. Barrier epithelial cells and the control of type 2 immunity. Immunity 43, 29–40 (2015). sourceNot checked — no full text of the source

Etokimab inhibited direct and CXCR1-dependent neutrophil migration in vitro.

“Etokimab inhibited direct, as well as CXCR1-dependent, neutrophil migration in vitro.”

• cites [68] Chen, Y. L. et al. Proof-of-concept clinical trial of etokimab shows a key role for IL-33 in atopic dermatitis pathogenesis. Sci. Transl Med. 11, eaax2945 (2019). sourceSupported

The improvement after a single dose of etokimab lasted for up to 140 days.

“Interestingly, this improvement lasted for up to 140 days after the single dose.”

• cites [68] Chen, Y. L. et al. Proof-of-concept clinical trial of etokimab shows a key role for IL-33 in atopic dermatitis pathogenesis. Sci. Transl Med. 11, eaax2945 (2019). sourcePartly supported

  The Efficacy section reports that clinical improvement after a single dose was sustained through day 57, but does not report that it lasted to day 140. Day 140 appears in the Pharmacodynamics section for an IgE measurement, not a clinical improvement outcome. Page numbers were unavailable in our copy. (LLM, conf=0.86)

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IL-1α has been considered a therapeutic target in atopic dermatitis.

“As one of the first and most important mediators in antigen presentation and induction of the inflammatory cascade, IL-1α has been considered as a therapeutic target in AD69.”

• cites [69] Archer, N. K. et al. Injury, dysbiosis, and filaggrin deficiency drive skin inflammation through keratinocyte IL-1alpha release. J. Allergy Clin. Immunol. 143, 1426–1443 (2019). sourceSupported

Tezepelumab has shown convincing results in patients with severe and uncontrolled allergic asthma.

“The anti-TSLP antibody tezepelumab (AMG 157) has shown convincing results in patients with severe and uncontrolled allergic asthma65,66.”

• cites [65] Menzies-Gow, A. et al. DESTINATION: a phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the long-term safety and tolerability of tezepelumab in adults and adolescents with severe, uncontrolled asthma. Respir. Res. 21, 279 (2020). sourcePartly supported

  The Background (page unavailable) reports that tezepelumab significantly reduced exacerbations and improved other outcomes in patients with severe, uncontrolled asthma. It does not identify those patients as having allergic asthma or report results specifically for that subgroup. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [66] Mullard, A. Tezepelumab prepares to enter the asthma antibody fray. Nat. Rev. Drug Discov. 20, 91 (2021). sourceNot checked — no full text of the source

In a mouse model, colonization with Staphylococcus aureus induces IL-36R- and IL-1R-dependent inflammation.

“Interestingly, in a mouse model, colonization with S. aureus induces IL-36R- and IL-1R-dependent inflammation73.”

• cites [73] Liu, H. et al. Staphylococcus aureus epicutaneous exposure drives skin inflammation via IL-36-mediated T cell responses. Cell Host Microbe 22, 653–666 (2017). Report on the direct impact of the microbiome on inflammation via the IL-36 pathway. sourcePartly supported

  In the Results section on IL-36R signaling (page unavailable), mice lacking IL-36R had substantially less skin inflammation after epicutaneous S. aureus exposure, supporting IL-36R dependence. The IL-1R-dependent part is not supported: mice lacking either IL-1α or IL-1β had inflammation measures similar to controls, and the paper distinguishes this epicutaneous response from the IL-1β response to intradermal infection. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

In patients with severe AD (SCORAD >50), fezakinumab produced a significantly greater mean decline in SCORAD than placebo.

“encouraging results were seen in patients with severe forms (SCORAD >50) where the mean decline in SCORAD was significantly better than in the placebo group122.”

• cites [122] Guttman-Yassky, E. et al. Efficacy and safety of fezakinumab (an IL-22 monoclonal antibody) in adults with moderate-to-severe atopic dermatitis inadequately controlled by conventional treatments: a randomized, double-blind, phase 2a trial. J. Am. Acad. Dermatol. 78, 872–881 (2018). sourceSupported

After re-randomization at week 16 and maintenance treatment, IGA 0/1 was reached by 51% in ECZTRA1 and 59% in ECZTRA2.

“after re-randomization at week 16 followed by maintenance treatment, the clinical response further improved, with IGA 0/1 being reached in 51% (ECZTRA1) and 59% (ECZTRA2) of the patients92.”

• cites [92] Wollenberg, A. et al. Tralokinumab for moderate-to-severe atopic dermatitis: results from two 52-week, randomized, double-blind, multicentre, placebo-controlled phase III trials (ECZTRA 1 and ECZTRA 2). Br. J. Dermatol. 184, 437–449 (2020). sourcePartly supported

  The Results (Maintenance outcomes at week 52) report IGA 0 or 1 in 51% of ECZTRA 1 patients and 59% of ECZTRA 2 patients who continued tralokinumab every two weeks after rerandomization. These percentages describe maintenance of response among patients who had already achieved IGA 0 or 1 at week 16, not a further improvement among patients generally. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

There is increasing evidence that the IL-23-IL-17 axis and IL-36 may have a role in some AD subtypes, such as the intrinsic form and in Asian patients.

“there is increasing evidence that the IL-23–IL-17 axis as well as IL-36 (see above) may have a role, at least in some AD subtypes such as the so-called intrinsic form and in Asian patients73,103,117,123–125.”

• cites [73] Liu, H. et al. Staphylococcus aureus epicutaneous exposure drives skin inflammation via IL-36-mediated T cell responses. Cell Host Microbe 22, 653–666 (2017). Report on the direct impact of the microbiome on inflammation via the IL-36 pathway. sourcePartly supported

  The Discussion (page unavailable) links IL-36 signaling to IL-17-producing T-cell responses in a mouse model of S. aureus-induced skin inflammation and relates the findings to human atopic dermatitis. It does not establish a role for the IL-23–IL-17 axis or address intrinsic atopic dermatitis or Asian patients, so the subtype-specific claim is not supported by this paper. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [103] Suarez-Farinas, M. et al. Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis. J. Allergy Clin. Immunol. 132, 361–370 (2013). sourcePartly supported

  The Results and Discussion report stronger IL-17/Th17 and IL-23-related activity in intrinsic than extrinsic atopic dermatitis, supporting a possible role for that axis in the intrinsic subtype. The paper mentions IL-36 only in discussing a proposed mechanism drawn from psoriasis research; it does not establish a role for IL-36 in atopic dermatitis or address Asian patients. Page numbers were not available in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [117] Esaki, H. et al. Early-onset pediatric atopic dermatitis is TH2 but also TH17 polarized in skin. J. Allergy Clin. Immunol. 138, 1639–1651 (2016). sourceNot checked — no full text of the source
• cites [123] Noda, S. et al. The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization. J. Allergy Clin. Immunol. 136, 1254–1264 (2015). The first report on TH17 immune polarization in Asian patients, questioning the dogma of the TH2 immune dominance in AD. sourceNot checked — no full text of the source
• cites [124] Czarnowicki, T. et al. Evolution of pathologic T-cell subsets in patients with atopic dermatitis from infancy to adulthood. J. Allergy Clin. Immunol. 145, 215–228 (2020). sourcePartly supported

  The Discussion reports an IL-17 signature in pediatric atopic dermatitis skin, providing limited support for a role for IL-17 in a subtype of the disease. It does not establish a role for the IL-23–IL-17 axis or IL-36, or address the intrinsic form or Asian patients; searches for those terms found no relevant passage. The cited copy provides no page numbers. (LLM, conf=0.78)

  Experimental — accuracy not yet measured
• cites [125] Renert-Yuval, Y. et al. The molecular features of normal and atopic dermatitis skin in infants, children, adolescents and adults. J. Allergy Clin. Immunol. 148, 148–163 (2021). sourcePartly supported

  The Results and Discussion report elevated IL-17 and other TH17-related markers in atopic dermatitis, particularly in infants, supporting a possible role for that pathway. The passages do not establish a role for IL-36 or address the specified intrinsic and Asian patient subtypes; searches for those terms did not find relevant passages. The cited paper studies age groups rather than those subtypes. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

In the entire fezakinumab study population, there was no significant difference in change in SCORAD from baseline as the primary end point.

“When considering the entire study population, there was no significant difference in the change of SCORAD compared with baseline as the primary end point.”

• cites [122] Guttman-Yassky, E. et al. Efficacy and safety of fezakinumab (an IL-22 monoclonal antibody) in adults with moderate-to-severe atopic dermatitis inadequately controlled by conventional treatments: a randomized, double-blind, phase 2a trial. J. Am. Acad. Dermatol. 78, 872–881 (2018). sourceSupported

IL-4 appears more relevant for the central part of the TH2 pathway.

“Whereas IL-4 seems to be more relevant for the central part of the TH2 pathway87”

• cites [87] Bao, K. & Reinhardt, R. L. The differential expression of IL-4 and IL-13 and its impact on type-2 immunity. Cytokine 75, 25–37 (2015). Important paper explaining the different roles and impacts of IL-4 and IL-13 within the TH2 immune response and inflammation. sourceSupported

IL-13 has been identified as the key TH2 cytokine mediating skin inflammation in AD.

“IL-13 has been identified as the key TH2 cytokine mediating the skin inflammation in AD88,89.”

• cites [88] Tsoi, L. C. et al. Atopic dermatitis is an IL-13-dominant disease with greater molecular heterogeneity compared to psoriasis. J. Invest. Dermatol. 139, 1480–1489 (2019). sourceSupported
• cites [89] Bieber, T. Interleukin-13: targeting an underestimated cytokine in atopic dermatitis. Allergy 75, 54–62 (2020). sourceNot checked — no full text of the source

Clinical improvement was shown in a small series of patients treated with omalizumab and/or immunoadsorption.

“clinical improvement was shown in a small series of patients using omalizumab and/or immunoadsorption109–112.”

• cites [109] Zink, A. et al. Targeting IgE in severe atopic dermatitis with a combination of immunoadsorption and omalizumab. Acta Derm. Venereol. 96, 72–76 (2016). sourceSupported
• cites [110] Hotze, M. et al. Increased efficacy of omalizumab in atopic dermatitis patients with wild-type filaggrin status and higher serum levels of phosphatidylcholines. Allergy 69, 132–135 (2014). sourceNot checked — no full text of the source
• cites [111] Lane, J. E., Cheyney, J. M., Lane, T. N., Kent, D. E. & Cohen, D. J. Treatment of recalcitrant atopic dermatitis with omalizumab. J. Am. Acad. Dermatol. 54, 68–72 (2006). sourceNot checked — no full text of the source
• cites [112] Holm, J. G., Agner, T., Sand, C. & Thomsen, S. F. Omalizumab for atopic dermatitis: case series and a systematic review of the literature. Int. J. Dermatol. 56, 18–26 (2017). sourceNot checked — no full text of the source

In a phase IIb dose-finding study, lebrikizumab 250 mg gave the best primary-end-point response, with 72% improvement versus 41% with placebo.

“In a phase IIb dose-finding study, the best clinical response for the primary end point (percentage change in EASI) was obtained with 250 mg. In this group, 72% improvement was shown versus 41% in the placebo group96.”

• cites [96] Guttman-Yassky, E. et al. Efficacy and safety of lebrikizumab, a high-affinity interleukin 13 inhibitor, in adults with moderate to severe atopic dermatitis: a phase 2b randomized clinical trial. JAMA Dermatol. 156, 411–420 (2020). sourceSupported

IL-22 is an important part of the transcriptomic signature in AD.

“IL-22 is an important part of the transcriptomic signature in AD116,117.”

• cites [116] Nograles, K. E. et al. IL-22-producing “T22” T cells account for upregulated IL-22 in atopic dermatitis despite reduced IL-17-producing TH17 T cells. J. Allergy Clin. Immunol. 123, 1244–1252 (2009). sourceSupported
• cites [117] Esaki, H. et al. Early-onset pediatric atopic dermatitis is TH2 but also TH17 polarized in skin. J. Allergy Clin. Immunol. 138, 1639–1651 (2016). sourceNot checked — no full text of the source

In vitro and animal-model evidence indicates that CRTH2 has an important role in TH2-mediated AD inflammation by directing migration into the skin.

“as shown in vitro and in animal models154,155, has an important role in TH2-mediated inflammation of AD by directing their migration into the skin.”

• cites [154] Boehme, S. A. et al. A small molecule CRTH2 antagonist inhibits FITC-induced allergic cutaneous inflammation. Int. Immunol. 21, 81–93 (2008). sourceNot checked — no full text of the source
• cites [155] He, R. et al. The prostaglandin D(2) receptor CRTH2 is important for allergic skin inflammation after epicutaneous antigen challenge. J. Allergy Clin. Immunol. 126, 784–790 (2010). sourcePartly supported

  The Introduction reports CRTH2-mediated chemotaxis in vitro, and the Results section on acute OVA challenge reports reduced skin infiltration by CD4+ cells and eosinophils in CRTH2-deficient mice (page numbers unavailable). But the Results on repeated sensitization find no important role for CRTH2 in chronic skin inflammation. The evidence therefore supports migration-related inflammation in an acute mouse model, not an unqualified role in AD inflammation. (LLM, conf=0.86)

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A maximal-use phase II study in Japanese children and adolescents confirmed the good safety and tolerance profile of difamilast.

“A maximal-use phase II study in Japanese children and adolescents confirmed the good safety and tolerance profile of this compound135.”

• cites [135] Saeki, H., Baba, N., Oshiden, K., Abe, Y. & Tsubouchi, H. Phase 2, randomized, double-blind, placebo-controlled, 4-week study to evaluate the safety and efficacy of OPA- 15406 (difamilast), a new topical selective phosphodiesterase type-4 inhibitor, in Japanese pediatric patients aged 2-14 years with atopic dermatitis. J. Dermatol. 47, 17–24 (2020). sourcePartly supported

  The Methods (Study design; page unavailable) describe a randomized, vehicle-controlled phase 2 study in Japan, not a maximal-use study. The Discussion (page unavailable) reports no serious treatment-emergent adverse events and suggests a favorable safety profile. The Introduction (page unavailable) attributes the maximal-use finding to a separate study conducted in the USA, so the claim conflates the two studies. (LLM, conf=0.90)

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PDE4 inhibitors have a wide spectrum of therapeutic effects related to downregulation of inflammatory cytokines in pulmonary, neurological, rheumatoid, gastrointestinal, and dermatological disorders.

“PDE4 inhibitors are known to have a wide spectrum of interesting therapeutic effects related to downregulation of inflammatory cytokines involved in pulmonary, neurological, rheumatoid, gastrointestinal and dermatological disorders128.”

• cites [128] Li, H., Zuo, J. & Tang, W. Phosphodiesterase-4 inhibitors for the treatment of inflammatory diseases. Front. Pharmacol. 9, 1048 (2018). sourceSupported

Pilot open-label studies of apremilast provided promising results.

“Pilot open-label studies of this PDE4 inhibitor provided promising results129,130.”

• cites [129] Samrao, A., Berry, T. M., Goreshi, R. & Simpson, E. L. A pilot study of an oral phosphodiesterase inhibitor (apremilast) for atopic dermatitis in adults. Arch. Dermatol. 148, 890–897 (2012). sourceSupported
• cites [130] Volf, E. M., Au, S. C., Dumont, N., Scheinman, P. & Gottlieb, A. B. A phase 2, open-label, investigator-initiated study to evaluate the safety and efficacy of apremilast in subjects with recalcitrant allergic contact or atopic dermatitis. J. Drugs Dermatol. 11, 341–346 (2012).Not checked — no full text of the source

Because neurons express IL-4 and IL-13 receptors, the early itch improvement seen with dupilumab, tralokinumab, or lebrikizumab supports a direct effect of these drugs on nerve endings.

“As neurons express receptors for IL-4 and IL-13, the early improvement of itch upon targeted therapy with dupilumab, tralokinumab or lebrikizumab supports the assumption of a direct effect of these drugs on nerve endings92,96,183.”

• cites [92] Wollenberg, A. et al. Tralokinumab for moderate-to-severe atopic dermatitis: results from two 52-week, randomized, double-blind, multicentre, placebo-controlled phase III trials (ECZTRA 1 and ECZTRA 2). Br. J. Dermatol. 184, 437–449 (2020). sourcePartly supported

  The Discussion (page not provided) reports that itch improved as early as week 1 with tralokinumab versus placebo. The paper does not establish neuronal IL-4 or IL-13 receptor expression or infer a direct effect on nerve endings; it also does not report early itch outcomes for dupilumab or lebrikizumab. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [96] Guttman-Yassky, E. et al. Efficacy and safety of lebrikizumab, a high-affinity interleukin 13 inhibitor, in adults with moderate to severe atopic dermatitis: a phase 2b randomized clinical trial. JAMA Dermatol. 156, 411–420 (2020). sourceSupported
• cites [183] Simpson, E. L. et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N. Engl. J. Med. 375, 2335–2348 (2016). Reports on the pivotal studies that have led to the approval of dupilumab as the first-in-class biologic for the therapy of AD. sourcePartly supported

  The Measures of Pruritus section (p. 6) reports significantly better itching scores with dupilumab than placebo by week 2, and the Background (p. 2) says dupilumab inhibits IL-4 and IL-13 signaling. The paper does not establish that neurons express those receptors, assess tralokinumab or lebrikizumab, or propose a direct effect on nerve endings. (LLM, conf=0.89)

  Experimental — accuracy not yet measured

• AssumptionRests on an assumption: Neurons express receptors for IL-4 and IL-13.

Substance P is involved in the initiation and transmission of itch through NK1R and MRGPRS expressed in the central nervous system and on various other cell types.

“Substance P is involved in the initiation and transmission of itch through the neurokinin 1 receptor (NK1R)195,196 and the Mas-related G protein-coupled receptor (MRGPRS)197,198 expressed in the central nervous system and on various other cell types.”

• cites [195] Steinhoff, M. S., von Mentzer, B., Geppetti, P., Pothoulakis, C. & Bunnett, N. W. Tachykinins and their receptors: contributions to physiological control and the mechanisms of disease. Physiol. Rev. 94, 265–301 (2014). sourcePartly supported

  The review’s “Dermatitis and pruritus” section (p. 20) identifies substance P as a mediator of itch in atopic dermatitis, and “Sensory Disorders of Pain and Pruritus” (p. 26) reports that NK1R antagonism reduced scratching or itch in the studies discussed. Its “NKR activation in DRG and spinal cord” section (p. 21) describes NK1R on spinal neurons, but the passages found do not support the claim that substance P acts through MRGPRs to initiate or transmit itch. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [196] Douglas, S. D. & Leeman, S. E. Neurokinin-1 receptor: functional significance in the immune system in reference to selected infections and inflammation. Ann. NY Acad. Sci. 1217, 83–95 (2011). sourcePartly supported

  The ‘Neurokinin 1 receptor’ section identifies NK1R as substance P’s preferred receptor and links their interaction to pain transmission. The ‘Substance P’ section reports substance P receptors on CNS cells. Neither passage establishes that the SP–NK1R pathway initiates or transmits itch; the separate MRGPRS citations are not attributed to this source. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [197] Azimi, E. et al. Dual action of neurokinin-1 antagonists on Mas-related GPCRs. JCI Insight 1, e89362 (2016). sourcePartly supported

  The Discussion (p. 5) reports that substance P–mediated scratching in mice correlates with Mrgpr activation, and that Mrgprs are expressed on sensory neurons and mast cells. The paper does not establish the claim that these receptors transmit itch in the central nervous system; its expression evidence concerns dorsal root ganglion neurons and mast cells. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

IL-31 signals through heterodimerization of IL-31Rα and OSMRβ.

“It signals through the heterodimerization of IL-31Rα and the oncostatin M receptor-β (OSMRβ)186,187.”

• cites [186] Jones, S. A. & Jenkins, B. J. Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer. Nat. Rev. Immunol. 18, 773–789 (2018). sourceSupported
• cites [187] Hermanns, H. M. Oncostatin M and interleukin-31: cytokines, receptors, signal transduction and physiology. Cytokine Growth Factor. Rev. 26, 545–558 (2015). sourceNot checked — no full text of the source

In a phase III study with 375 patients, the NK1R antagonist tradipitant missed the primary end point of reduction in pruritus.

“In a phase III study with 375 patients, another novel NK1R antagonist tradipitant (VLY-686) (EPIONE study), missed the primary end point of reduction in pruritus.”

• cites [206] Welsh, S. E. et al. Neurokinin-1 receptor antagonist tradipitant has mixed effects on itch in atopic dermatitis: results from EPIONE, a randomized clinical trial. J. Eur. Acad. Dermatol. Venereol. 35, e338–e340 (2021). sourceSupported

After successful phase III studies, topical delgocitinib ointment was approved in 2020 for moderate to severe atopic dermatitis in Japan.

“After successful phase III studies224,225, topical delgocitinib ointment was approved in 2020 for moderate to severe AD in Japan226.”

• cites [224] Nakagawa, H. et al. Delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with moderate to severe atopic dermatitis: a phase 3, randomized, double-blind, vehicle-controlled study and an open-label, long-term extension study. J. Am. Acad. Dermatol. 82, 823–831 (2020). sourceNot checked — no full text of the source
• cites [225] Nakagawa, H. et al. Long-term safety and efficacy of delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with atopic dermatitis. J. Dermatol. 47, 114–120 (2020). sourceCould not verify

  Citation 226 is attached to the approval claim, not the preceding phase III results. The Introduction and Discussion describe Japanese delgocitinib studies and their efficacy, but our copy does not state that the ointment was approved in 2020 or specify an approved indication; searches for approval and 2020 found no such passage. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [226] Dhillon, S. Delgocitinib: first approval. Drugs 80, 609–615 (2020). sourceNot checked — no full text of the source

Abrocitinib showed similar significant results in phase III studies.

“The other JAK1-selective JAKi abrocitinib showed similar significant results in phase III238 studies.”

• cites [238] Simpson, E. L. et al. Efficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (JADE MONO-1): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet 396, 255–266 (2020). Report on a pivotal study showing the good results obtained with the JAK1 inhibitor abrocitinib in AD. sourceSupported

SYK is a crucial signalling molecule for the high-affinity IgE receptor expressed on epidermal Langerhans cells and inflammatory dendritic epidermal cells.

“Besides T cell activation, SYK is a crucial signalling molecule for the high-affinity receptor for IgE (FcεRI) expressed on epidermal Langerhans cells and inflammatory dendritic epidermal cells229–231.”

• cites [229] Bieber, T. et al. Human epidermal Langerhans cells express the high affinity receptor for immunoglobulin E (Fc epsilon RI). J. Exp. Med. 175, 1285–1290 (1992). sourcePartly supported

  The Summary (p. 1285) states that epidermal Langerhans cells express FcεRI, and the results (p. 1286) identify FcεRI-positive epidermal dendritic cells as Langerhans cells. The cited paper does not establish SYK’s signalling role or address inflammatory dendritic epidermal cells. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [230] Jurgens, M., Wollenberg, A., Hanau, D., de la Salle, H. & Bieber, T. Activation of human epidermal Langerhans cells by engagement of the high affinity receptor for IgE, Fc epsilon RI. J. Immunol. 155, 5184–5189 (1995). sourceNot checked — no full text of the source
• cites [231] Klaeschen, A. S. et al. JAK1/2 inhibition impairs the development and function of inflammatory dendritic epidermal cells in atopic dermatitis. J. Allergy Clin. Immunol. 147, 2202–2212.e8 (2020). sourceNot checked — no full text of the source

In that phase III study, a 50% reduction in SCORAD from baseline was noticed in mild forms of atopic dermatitis.

“However, reduction of 50% in SCORAD from baseline was noticed in mild forms of AD206.”

• cites [206] Welsh, S. E. et al. Neurokinin-1 receptor antagonist tradipitant has mixed effects on itch in atopic dermatitis: results from EPIONE, a randomized clinical trial. J. Eur. Acad. Dermatol. Venereol. 35, e338–e340 (2021). sourcePartly supported

  The Figure 2 caption reports that a greater proportion of patients with mild atopic dermatitis achieved at least 50% improvement on SCORAD; it does not report a 50% reduction for the mild subgroup overall. The discussion also says there was no significant SCORAD index improvement in the early weeks. Our copy provides no page number for either passage. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

Depending on their dose-dependent selectivity for one or several JAKs, JAK inhibitors exert a broad immunopharmacological impact by blocking signal transduction pathways of multiple type I and type II cytokine receptors.

“Depending on their dose-dependent selectivity for one or several JAKs, the JAK inhibitors (JAKi) exert a broad immunopharmacological impact because they block the signal transduction pathways of multiple type I (haematopoietic family) and type II (interferon) cytokine receptors17,214.”

• cites [17] Schwartz, D. M. et al. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat. Rev. Drug Discov. 16, 843–862 (2017). Excellent review on the mode of action of JAK inhibitors. sourceSupported
• cites [214] Spangler, J. B., Moraga, I., Mendoza, J. L. & Garcia, K. C. Insights into cytokine-receptor interactions from cytokine engineering. Annu. Rev. Immunol. 33, 139–167 (2015). sourcePartly supported

  The Introduction (page unavailable) says cytokine–receptor complexes activate associated JAKs, and the type I interferon section identifies JAK1 and TYK2 in interferon-receptor signaling. The paper does not establish the claimed dose-dependent selectivity of JAK inhibitors or their broad blocking effects across type I and type II cytokine receptors. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

In the pivotal monotherapy studies JADE-MONO-1 and JADE-MONO-2, the primary end point IGA 0/1 was reached with abrocitinib.

“In the pivotal monotherapy studies (JADE-MONO-1 and JADE-MONO-2), the primary end point IGA 0/1 was reached.”

• cites [238] Simpson, E. L. et al. Efficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (JADE MONO-1): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet 396, 255–266 (2020). Report on a pivotal study showing the good results obtained with the JAK1 inhibitor abrocitinib in AD. sourcePartly supported

  The Summary (p. 2) identifies IGA 0/1, with at least a two-grade improvement, as a coprimary endpoint of JADE MONO-1 and reports significantly higher response rates with both abrocitinib doses than with placebo. This paper reports JADE MONO-1, not JADE MONO-2, so it does not establish the claimed result for both studies. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Petrolatum has been shown to modulate antimicrobial and epidermal barrier function.

“In line with this concept, even a simple product such as petrolatum has been shown to modulate the antimicrobial and epidermal barrier function47.”

• cites [47] Czarnowicki, T. et al. Petrolatum: barrier repair and antimicrobial responses underlying this “inert” moisturizer. J. Allergy Clin. Immunol. 137, 1091–1102 (2016). sourceNot checked — no full text of the source

The main cellular and soluble components involved in atopic dermatitis pathophysiology are key targets of current pharmacological intervention.

“The main cellular and soluble components involved in the pathophysiology of AD represent the key targets of current efforts in pharmacological intervention (Fig. 2).”

In a phase IIa randomized controlled trial in adults, B244 given as a spray induced a significant improvement of pruritus.

“In a phase IIa randomized controlled trial (RCT) in adults, B244 given as a spray induced a significant improvement of the pruritus.”

• cites AOBiome press releaseNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

A similar effect on itching was reported in an open-label phase Ib paediatric trial of B244.

“A similar effect on itching was reported in an open-label phase Ib paediatric trial (see the press release from AOBiome in Related links).”

• cites AOBiome press releaseNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The mechanism by which Langerhans cells educate the adaptive immune system is defective in atopic dermatitis.

“The latter mechanism is defective in AD250.”

• cites [250] Iwamoto, K. et al. Langerhans and inflammatory dendritic epidermal cells in atopic dermatitis are tolerized toward TLR2 activation. Allergy 73, 2205–2213 (2018). The first report that epidermal DCs isolated from AD skin are tolerant to S. aureus-derived signals. sourceNot checked — no full text of the source

Dupilumab and tralokinumab are targeted biologic therapies that specifically address a distinct immune pathway and its cytokines or receptors.

“Dupilumab and tralokinumab are examples of targeted biologic therapies that specifically address a distinct immune pathway and its cytokines or receptors16,”

• cites [16] Wu, J. & Guttman-Yassky, E. Efficacy of biologics in atopic dermatitis. Expert Opin. Biol. Ther. 20, 525–538 (2020). sourceNot checked — no full text of the source

In the past two decades, progress in understanding the phenotype and mechanisms of atopic dermatitis has offered multiple new potential targets for pharmacological intervention.

“In the past two decades, significant progress has been made in our understanding of the complex phenotype and mechanisms that underlie AD18, offering multiple new potential targets for pharmacological intervention19.”

• cites [18] Weidinger, S., Beck, L. A., Bieber, T., Kabashima, K. & Irvine, A. D. Atopic dermatitis. Nat. Rev. Dis. Prim. 4, 1 (2018). A key review paper on the current understanding of the pathophysiology of AD. sourceNot checked — no full text of the source
• cites [19] Paller, A. S., Kabashima, K. & Bieber, T. Therapeutic pipeline for atopic dermatitis: end of the drought? J. Allergy Clin. Immunol. 140, 633–643 (2017). sourceNot checked — no full text of the source

In a phase IIa trial, a low-dose KY1005 regimen produced a mean EASI percentage change from baseline of 80.1%, compared with 49.4% for placebo.

“A low-dose regimen resulted in a mean percentage change of EASI from baseline of 80.1% versus 49.4% in the placebo group.”

• cites Kymab press bulletinNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In a phase IIa study in patients with atopic dermatitis, 64.7% of patients reached EASI50 versus 48.2% in the placebo group.

“By contrast, a phase IIa study in patients with AD showed 64.7% of patients reaching the EASI50 end point versus 48.2% in the placebo group67.”

• cites [67] Simpson, E. L. et al. Tezepelumab, an anti-thymic stromal lymphopoietin monoclonal antibody, in the treatment of moderate to severe atopic dermatitis: a randomized phase 2a clinical trial. J. Am. Acad. Dermatol. 80, 1013–1021 (2019). sourceNot checked — no full text of the source

No safety signals were reported for CBP-201.

“There were no safety signals reported”

Interpretation of the tezepelumab atopic dermatitis data is difficult because all patients were allowed to use topical corticosteroids.

“However, the interpretation of these data is difficult as all patients were allowed to use TCSs.”

CBP-201 produced a mean EASI reduction from baseline of 74%, versus 33% with placebo.

“The mean reduction in EASI from baseline was 74% versus 33% in the placebo group.”

After 4 weeks of CBP-201 therapy, IGA 0/1 was reached by up to 50% of patients, versus 13% with placebo.

“After only 4 weeks of therapy, IGA 0/1 was seen in up to 50% of patients receiving CBP-201 versus 13% in the placebo group.”

These data suggest that tapinarof represents a promising new option for topical therapy of both atopic dermatitis and psoriasis.

“These data suggest that this compound represents a promising new option for topical therapy of both AD and psoriasis63, another chronic inflammatory skin disorder.”

• cites [63] Stein Gold, L., Bhatia, N., Tallman, A. M. & Rubenstein, D. S. A phase 2b, randomized clinical trial of tapinarof cream for the treatment of plaque psoriasis: secondary efficacy and patient-reported outcomes. J. Am. Acad. Dermatol. 84, 624–631 (2020). sourceNot checked — no full text of the source

In a larger phase IIa study (ATLAS) with 300 adult patients, the primary end point was not reached.

“However, in a larger phase IIa study (ATLAS study) with 300 adult patients, the primary end point was not reached (see the press release from AnaptysBio in Related links).”

• cites AnaptysBio press releaseNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

IL-36 is upregulated in the skin of psoriasis as well as atopic dermatitis.

“IL-36 is another player in the innate immune system that is upregulated in the skin of psoriasis as well as AD.”

Dupilumab binds IL-4Rα, the shared chain of the type I and type II receptors for IL-4 and IL-13.

“Dupilumab binds to IL-4Rα, the chain common to the type I (IL-4Rα/IL-2Rγ) and type II (IL-4Rα/IL-13Rα1) receptors for IL-4 and IL-13”

• cites refs81,82Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

CBP-201 appears to have a faster onset of action than dupilumab.

“Although the mode of action is theoretically similar to that of dupilumab, it seems to have a faster onset of action.”

GBR 830 also improved the gene signatures in the skin.

“The antibody also improved the gene signatures in the skin78.”

• cites [78] Guttman-Yassky, E. et al. GBR 830, an anti-OX40, improves skin gene signatures and clinical scores in patients with atopic dermatitis. J. Allergy Clin. Immunol. 144, 482–493 (2019). First report on the therapeutic potential of a targeted therapy aiming to impact antigen presentation. sourceNot checked — no full text of the source

AhR exerts pro- and anti-inflammatory activities depending on the cell type, micromilieu, and ligand.

“It exerts pro- and anti-inflammatory activities, depending on the cell type, the micromilieu and the ligand, that is, exogenous and endogenous metabolites and agents58.”

• cites [58] Trikha, P. & Lee, D. A. The role of AhR in transcriptional regulation of immune cell development and function. Biochim. Biophys. Acta Rev. Cancer 1873, 188335 (2020). sourceNot checked — no full text of the source

The underlying march of the adaptive immune system starts from antigen presentation and affects various pathways, ultimately offering distinct therapeutic options.

“The underlying ‘march of the adaptive immune system’ starts from antigen presentation and affects varrious pathways, ultimately offering distinct therapeutic options18,19,75–77.”

• cites [18] Weidinger, S., Beck, L. A., Bieber, T., Kabashima, K. & Irvine, A. D. Atopic dermatitis. Nat. Rev. Dis. Prim. 4, 1 (2018). A key review paper on the current understanding of the pathophysiology of AD. sourceNot checked — no full text of the source
• cites [19] Paller, A. S., Kabashima, K. & Bieber, T. Therapeutic pipeline for atopic dermatitis: end of the drought? J. Allergy Clin. Immunol. 140, 633–643 (2017). sourceNot checked — no full text of the source
• cites [75] Brunner, P. M. Early immunologic changes during the onset of atopic dermatitis. Ann. Allergy Asthma Immunol. 123, 152–157 (2019). sourceNot checked — no full text of the source
• cites [76] Brunner, P. M. et al. The blood proteomic signature of early-onset pediatric atopic dermatitis shows systemic inflammation and is distinct from adult, longstanding disease. J. Am. Acad. Dermatol. 81, 510–519 (2019). sourceNot checked — no full text of the source
• cites [77] Zhou, L. et al. Age-specific changes in the molecular phenotype of patients with moderate-to-severe atopic dermatitis. J. Allergy Clin. Immunol. 144, 144–156 (2019). sourceNot checked — no full text of the source

The heterogeneity of the clinical phenotype of atopic dermatitis most probably reflects the highly complex pathophysiology.

“The heterogeneity of the clinical phenotype of AD most probably reflects the highly complex pathophysiology.”

Because AhR is expressed in keratinocytes and resident epidermal dendritic cells, it represents an ideal target for a topical pharmacological approach.

“As it is expressed in keratinocytes and resident epidermal dendritic cells (DCs), AhR represents an ideal target for a topical pharmacological approach.”

In the KY1005 phase IIa trial, IGA 0/1 was achieved by 44% of KY1005 recipients and 8% of placebo recipients.

“IGA 0/1 was reached in 44% of those who received KY1005 versus 8% in the placebo group”

• cites Kymab press bulletinNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The aryl-hydrocarbon receptor is a ligand-activated transcriptional factor with a Janus-faced role in physiology and pathophysiology of several skin disorders including atopic dermatitis.

“The aryl-hydrocarbon receptor (AhR) is a ligand-activated transcriptional factor with a Janus-faced role in physiology and the pathophysiology of several skin disorders including AD56,57.”

• cites [56] Haarmann-Stemmann, T., Esser, C. & Krutmann, J. The Janus-faced role of aryl hydrocarbon receptor signaling in the skin: consequences for prevention and treatment of skin disorders. J. Invest. Dermatol. 135, 2572–2576 (2015). sourceNot checked — no full text of the source
• cites [57] Hidaka, T. et al. The aryl hydrocarbon receptor AhR links atopic dermatitis and air pollution via induction of the neurotrophic factor artemin. Nat. Immunol. 18, 64–73 (2017). Important paper reporting on the role of the xenobiotic receptor AhR in sensing environmental factors to induce AD lesions in an animal model. sourceNot checked — no full text of the source

Limited efficacy observed in some studies targeting TSLP or IL-33 may not predict their efficacy in an early phase of atopic dermatitis, that is, in the paediatric population.

“As, for regulatory reasons, proof-of-concept studies are primarily performed in adults, the limited efficacy observed in some studies such as those targeting TSLP or IL-33 may not predict their efficacy in an early phase of the disease, that is, in the paediatric population.”

Alarmins are interesting therapeutic targets given their key role in initiation of the skin-derived immune response.

“Given their key role in initiation of the skin-derived immune response, alarmins are interesting therapeutic targets.”

In the two tralokinumab phase III trials, EASI75 was reached by 25% and 33% of treated patients, versus 13% and 11% with placebo.

“Similarly, EASI75 was reached in 25% and 33% of patients receiving treatment in the two trials versus 13% and 11% receiving placebo, respectively.”

In the ADAPT study, weight-adapted omalizumab in children with high total serum IgE produced a significant difference in change from baseline in objective SCORAD versus placebo.

“using weight-adapted doses of omalizumab in children with high total serum IgE, there was a significant difference in the change from baseline for the objective SCORAD as primary end point compared with the placebo group114.”

• cites [114] Chan, S., Cornelius, V., Cro, S., Harper, J. I. & Lack, G. Treatment effect of omalizumab on severe pediatric atopic dermatitis: the ADAPT randomized clinical trial. JAMA Pediatr. 174, 29–37 (2019). sourceNot checked — no full text of the source

Omalizumab failed to show convincing results in proof-of-concept studies and single cases.

“strategies aimed at depleting IgE with the anti-IgE biologic omalizumab failed to show convincing results in proof-of-concept studies and single cases107,108.”

• cites [107] Heil, P. M., Maurer, D., Klein, B., Hultsch, T. & Stingl, G. Omalizumab therapy in atopic dermatitis: depletion of IgE does not improve the clinical course - a randomized, placebo-controlled and double blind pilot study. J. Dtsch. Dermatol. Ges. 8, 990–998 (2010). sourceNot checked — no full text of the source
• cites [108] Krathen, R. A. & Hsu, S. Failure of omalizumab for treatment of severe adult atopic dermatitis. J. Am. Acad. Dermatol. 53, 338–340 (2005). sourceNot checked — no full text of the source

Tralokinumab may reach its full potential at a later time point.

“This suggests that tralokinumab develops its full potential at a later time point.”

In ECZTRA1 and ECZTRA2 at week 16, the mean rate of eye disorders with tralokinumab was 7.6%, versus 3% with placebo.

“The mean rate of eye disorders for both ECZTRA1 and ECZTRA2 studies with tralokinumab at week 16 was 7.6% versus 3% in the placebo group.”

Similar results were obtained for the EASI score in the ADAPT study.

“Similar results were obtained for the EASI score.”

Lebrikizumab impairs heterodimerization of IL-4Rα and IL-13Rα1, thereby inhibiting signal transduction.

“Lebrikizumab is another fully humanized anti-IL-13 antibody that does not block the binding of the cytokine to the receptor but instead impairs the heterodimerization of IL-4Rα and IL-13Rα1, thereby inhibiting signal transduction91,95.”

• cites [91] May, R. D. & Fung, M. Strategies targeting the IL-4/IL-13 axes in disease. Cytokine 75, 89–116 (2015). sourceNot checked — no full text of the source
• cites [95] Ultsch, M. et al. Structural basis of signaling blockade by anti-IL-13 antibody lebrikizumab. J. Mol. Biol. 425, 1330–1339 (2013). sourceNot checked — no full text of the source

These observations imply a role for IgE-bearing antigen-presenting epidermal dendritic cells, such as Langerhans cells, in capturing and presenting allergens to T cells.

“These observations imply a role for IgE-bearing antigen-presenting epidermal DCs such as Langerhans cells in the capture and presentation of allergens to T cells106.”

• cites [106] Novak, N. et al. FcεRI engagement of Langerhans cell-like dendritic cells and inflammatory dendritic epidermal cell-like dendritic cells induces chemotactic signals and different T-cell phenotypes in vitro. J. Allergy Clin. Immunol. 113, 949–957 (2004). sourceNot checked — no full text of the source

IL-22 is induced by staphylococcal exotoxins in numerous inflammatory cells, including TH1 and TH17 cells.

“This cytokine is induced by staphylococcal exotoxins118 in numerous inflammatory cells, including TH1 and TH17 cells.”

• cites [118] Niebuhr, M., Scharonow, H., Gathmann, M., Mamerow, D. & Werfel, T. Staphylococcal exotoxins are strong inducers of IL-22: a potential role in atopic dermatitis. J. Allergy Clin. Immunol. 126, 1176–1183 (2010). sourceNot checked — no full text of the source

Lebrikizumab efficacy was accompanied by rapid improvement in the pruritus NRS.

“The efficacy was mirrored by a rapid improvement in the pruritus NRS.”

Targeting membrane IgE would lead to long-term reduction in IgE-mediated reactions in allergic individuals, including AD patients.

“This approach would lead to long-term reduction in IgE-mediated reactions in allergic individuals, including patients with AD115.”

• cites [115] Liour, S. S., Tom, A., Chan, Y. H. & Chang, T. W. Treating IgE-mediated diseases via targeting IgE-expressing B cells using an anti-CεmX antibody. Pediatr. Allergy Immunol. 27, 446–451 (2016). Explains the strategy of depleting IgE-committed B cells by targeting membrane IgE. sourceNot checked — no full text of the source

Provocation tests with food allergens or aeroallergens induce exacerbation in a subgroup of AD patients.

“provocation tests with food allergens as well as with aeroallergens induce exacerbation in a subgroup of AD patients104,105.”

• cites [104] Werfel, T. et al. Exacerbation of atopic dermatitis on grass pollen exposure in an environmental challenge chamber. J. Allergy Clin. Immunol. 136, 96–103 (2015). Further evidence for a role of IgE-mediated allergy to aeroallergens in AD. sourceNot checked — no full text of the source
• cites [105] Roerdink, E. M. et al. Association of food allergy and atopic dermatitis exacerbations. Ann. Allergy Asthma Immunol. 116, 334–338 (2016). sourceNot checked — no full text of the source

Antigen-specific TH2 cells are a numerically important component of dermal and epidermal infiltrates in AD.

“Antigen-specific TH2 cells represent a numerically important component of the dermal and epidermal infiltrates in AD18.”

• cites [18] Weidinger, S., Beck, L. A., Bieber, T., Kabashima, K. & Irvine, A. D. Atopic dermatitis. Nat. Rev. Dis. Prim. 4, 1 (2018). A key review paper on the current understanding of the pathophysiology of AD. sourceNot checked — no full text of the source

Difamilast cream was effective in adolescents and adults in a phase IIa study.

“Difamilast (OPA-15406/MM36) administered as a cream has been shown to be effective in adolescents and adults in a phase IIa study134.”

• cites [134] Hanifin, J. M. et al. OPA-15406, a novel, topical, nonsteroidal, selective phosphodiesterase-4 (PDE4) inhibitor, in the treatment of adult and adolescent patients with mild to moderate atopic dermatitis (AD): a phase-II randomized, double-blind, placebo-controlled study. J. Am. Acad. Dermatol. 75, 297–305 (2016). sourceNot checked — no full text of the source

T cells contribute to a dynamic, disease-specific inflammatory micromilieu that strongly impacts epidermal barrier function.

“By the production of a large variety of mediators, T cells contribute to the generation of a dynamic and disease-specific inflammatory micromilieu with a strong impact on epidermal barrier function.”

The promising difamilast results were confirmed in two phase III pivotal trials completed in Japan.

“These promising results were confirmed in two phase III pivotal trials completed in Japan (see the press release in Related links).”

• cites press releaseNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In animal models, RPT193 activity was similar to that of an anti-IL-13 antibody.

“In these animal models, the activity was similar to that of an anti-IL-13 antibody”

• cites Rapt Therapeutics Form 8-KNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

CRTH2 is preferentially expressed on TH2 cells.

“CRTH2 is preferentially expressed on TH2 cells152,153”

• cites [152] Cosmi, L. et al. CRTH2 is the most reliable marker for the detection of circulating human type 2Th and type 2 T cytotoxic cells in health and disease. Eur. J. Immunol. 30, 2972–2979 (2000). sourceNot checked — no full text of the source
• cites [153] Iwasaki, M. et al. Association of a new-type prostaglandin D2 receptor CRTH2 with circulating T helper 2 cells in patients with atopic dermatitis. J. Invest. Dermatol. 119, 609–616 (2002). sourceNot checked — no full text of the source

Lotamilast in a cream showed promising results in Japanese adults and children.

“Promising results have been obtained initially with lotamilast (RVT-501/E6005) in a cream in Japanese adults and children132,133.”

• cites [132] Furue, M. et al. Safety and efficacy of topical E6005, a phosphodiesterase 4 inhibitor, in Japanese adult patients with atopic dermatitis: results of a randomized, vehicle-controlled, multicenter clinical trial. J. Dermatol. 41, 577–585 (2014). sourceNot checked — no full text of the source
• cites [133] Nemoto, O. et al. Effect of topical phosphodiesterase 4 inhibitor E6005 on Japanese children with atopic dermatitis: results from a randomized, vehicle-controlled exploratory trial. J. Dermatol. 43, 881–887 (2016). sourceNot checked — no full text of the source

The CRTH2 antagonists fevipiprant and temapiprant failed to significantly improve AD in phase II studies.

“both CRTH2 antagonists fevipiprant (QAW039) and temapiprant (OC000459) failed to significantly improve AD in phase II studies.”

In preclinical experiments, the small-molecule CCR4 antagonist RPT193 selectively blocks recruitment of TH2 cells in allergic diseases.

“In preclinical experiments, RPT193, a small-molecule CCR4 antagonist, selectively blocks the recruitment of TH2 cells in allergic diseases.”

• cites Rapt Therapeutics Form 8-KNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Topical administration of PDE4 inhibitors avoids the typical gastrointestinal adverse events seen with systemic application.

“An alternative approach is the topical administration of PDE4 inhibitors, thereby avoiding the typical gastrointestinal adverse events observed with systemic application.”

In a phase I study, RPT193 caused no serious adverse events in 64 healthy subjects after single and multiple dosing.

“First reports from a phase I study showed no serious adverse events in 64 healthy subjects after single and multiple dosing”

• cites RAPT Therapeutics press releaseNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Prostaglandin D2 and its receptor play an important role in generating inflammation.

“Prostaglandin D2 and its receptor (PGDR2/CRTH2) play an important role in the generation of inflammation151.”

• cites [151] Marone, G. et al. Prostaglandin D2 receptor antagonists in allergic disorders: safety, efficacy, and future perspectives. Expert Opin. Investig. Drugs 28, 73–84 (2019). Interesting review on the pharmacology of PGD2 receptor antagonists. sourceNot checked — no full text of the source

Etrasimod was overall well tolerated.

“Etrasimod was overall well tolerated”

In a phase IIa study, the anti-IL-31Rα antibody nemolizumab significantly decreased the pruritus sensation.

“In a phase IIa study, the anti-IL-31Rα antibody nemolizumab led to a significant decrease in the pruritus sensation”

• cites [189] Ruzicka, T. et al. Anti-interleukin-31 receptor a antibody for atopic dermatitis. N. Engl. J. Med. 376, 826–835 (2017). sourceNot checked — no full text of the source

In the phase IIb ADVISE trial, etrasimod achieved the primary end point vIGA 0/1 in 36.8% of patients, versus 13% with placebo.

“In the phase IIb ADVISE trial, etrasimod achieved the primary end point validated IGA (vIGA) 0/1 in 36.8% versus 13% in the placebo group.”

• cites press statementNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Interpretation of the nemolizumab long-term extension is challenging because of concomitant topical corticosteroid use and the absence of a placebo arm.

“However, the concomitant use of TCSs and the lack of placebo arm in this extension study makes the interpretation challenging.”

Etrasimod did not induce cardiovascular toxicity commonly seen with this drug class.

“the drug did not induce adverse events such as cardiovascular toxicity commonly seen with this class of compound.”

Nemolizumab generated promising results in prurigo nodularis, a highly pruritic skin disorder assumed to be related to atopic dermatitis.

“Of note, nemolizumab generated promising results in prurigo nodularis, a highly pruritic skin disorder assumed to be related to AD193.”

• cites [193] Stander, S. et al. Trial of nemolizumab in moderate-to-severe prurigo nodularis. N. Engl. J. Med. 382, 706–716 (2020). Report on the efficacy of the anti-IL-31 biologic nemolizumab in prurigo nodularis. sourceNot checked — no full text of the source

• AssumptionThe authors state this as an assumption: Prurigo nodularis is related to atopic dermatitis.

In the same long-term extension, clinical improvement was achieved in a dose-independent fashion.

“while achieving clinical improvement in a dose-independent fashion190.”

• cites [190] Kabashima, K. et al. Nemolizumab in patients with moderate-to-severe atopic dermatitis: randomized, phase II, long-term extension study. J. Allergy Clin. Immunol. 142, 1121–1130 (2018). sourceNot checked — no full text of the source

In the 52-week long-term extension of the nemolizumab study, efficacy against itching was confirmed.

“In the 52-week long-term extension of this study, the efficacy towards itching was confirmed”

• cites [190] Kabashima, K. et al. Nemolizumab in patients with moderate-to-severe atopic dermatitis: randomized, phase II, long-term extension study. J. Allergy Clin. Immunol. 142, 1121–1130 (2018). sourceNot checked — no full text of the source

In another phase II study, nemolizumab produced an early improvement in itching as measured by a decrease in PP-NRS of 69% versus 34%.

“In another phase II study, the expected early improvement in itching was captured by the decrease in PP-NRS (69% versus 34%).”

• cites [191] Silverberg, J. I. et al. Phase 2B randomized study of nemolizumab in adults with moderate-to-severe atopic dermatitis and severe pruritus. J. Allergy Clin. Immunol. 145, 173–182 (2020). sourceNot checked — no full text of the source

In the same phase IIa study, nemolizumab did not significantly improve overall clinical inflammation as measured by BSA, EASI and IGA at that time point.

“but the overall clinical inflammation as evaluated by the body surface area (BSA), EASI and IGA scorings did not improve significantly at this time point189.”

• cites [189] Ruzicka, T. et al. Anti-interleukin-31 receptor a antibody for atopic dermatitis. N. Engl. J. Med. 376, 826–835 (2017). sourceNot checked — no full text of the source

Targeting IL-31 and its receptor is a focus of strategies to better control itching.

“Targeting IL-31 and its receptor is a focus of strategies to better control itching188.”

• cites [188] Nakashima, C., Otsuka, A. & Kabashima, K. Interleukin-31 and interleukin-31 receptor: new therapeutic targets for atopic dermatitis. Exp. Dermatol. 27, 327–331 (2018). sourceNot checked — no full text of the source

In a phase III study over 16 weeks, nemolizumab in combination with topical corticosteroids reduced pruritus by 43% versus 21% in the placebo group as measured by the visual analogue scale.

“The overall efficacy in pruritus in combination with TCSs was further confirmed in a phase III study over 16 weeks with a decrease of 43% versus 21% in the placebo group as measured by the visual analogue scale score.”

• cites [192] Kabashima, K., Matsumura, T., Komazaki, H. & Kawashima, M., Nemolizumab-JP01 Study Group. Trial of nemolizumab and topical agents for atopic dermatitis with pruritus. N. Engl. J. Med. 383, 141–150 (2020). sourceNot checked — no full text of the source

Topical fingolimod has been reported to reduce allergic inflammation in animal models of skin disorders.

“The topical application of the prototypical S1PR agonist fingolimod (mol. wt 343) has been reported to reduce allergic inflammation in animal models of skin disorders169–171.”

• cites [169] Tsuji, T. et al. Therapeutic approach to mite-induced intractable dermatitis using novel immunomodulator FTY720 ointment (fingolimod) in NC/Nga mice. Allergol. Int. 65, 172–179 (2016). sourceNot checked — no full text of the source
• cites [170] Schaper, K. et al. Sphingosine-1-phosphate exhibits anti-proliferative and anti-inflammatory effects in mouse models of psoriasis. J. Dermatol. Sci. 71, 29–36 (2013). sourceNot checked — no full text of the source
• cites [171] Park, S. J. & Im, D. S. Blockage of sphingosine-1-phosphate receptor 2 attenuates 2,4-dinitrochlorobenzene-induced atopic dermatitis in mice. Acta Pharmacol. Sin. 41, 1487–1496 (2020). sourceNot checked — no full text of the source

In that phase III study, the EASI score showed a moderate improvement of 46% with nemolizumab versus 33% in the placebo group.

“The EASI score showed a moderate improvement of 46% with nemolizumab versus 33% in the placebo group192.”

• cites [192] Kabashima, K., Matsumura, T., Komazaki, H. & Kawashima, M., Nemolizumab-JP01 Study Group. Trial of nemolizumab and topical agents for atopic dermatitis with pruritus. N. Engl. J. Med. 383, 141–150 (2020). sourceNot checked — no full text of the source

In that phase II study, IGA 0/1 was reached in 33% of nemolizumab-treated patients versus 12% in the placebo group at week 16.

“IGA 0/1 was reached in 33% of the patients versus 12% in the placebo group at week 16”

• cites [191] Silverberg, J. I. et al. Phase 2B randomized study of nemolizumab in adults with moderate-to-severe atopic dermatitis and severe pruritus. J. Allergy Clin. Immunol. 145, 173–182 (2020). sourceNot checked — no full text of the source

Vixarelimab had no significant effect on EASI and SCORAD.

“However, there was no significant effect on EASI and SCORAD194.”

• cites [194] Mihak, Z. et al. KPL-716, anti-Oncostatin M receptor beta antibody, reduced pruritus in atopic dermatitis [abstract 560]. J. Invest. Dermatol. 139 (Suppl.), S96 (2019). sourceNot checked — no full text of the source

Currently available data suggest that in atopic dermatitis, itching is a result of inflammation.

“Currently available data suggest that in AD, itching is a result of inflammation.”

In the BREEZE-AD1 study, baricitinib achieved the primary end point IGA 0/1 in 17% of patients versus 5% for placebo.

“In this population, the primary end point IGA 0/1 was reached in 17% versus 5% for placebo (BREEZE-AD1 study)”

• cites [235] Simpson, E. L. et al. Baricitinib in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: results from two randomised monotherapy phase 3 trials. Br. J. Dermatol. 183, 242–255 (2020). sourceNot checked — no full text of the source

In a large phase II study (ATOMIK, 484 participants) in atopic dermatitis, serlopitant missed the primary end point of change in worst itch NRS from baseline.

“However, in another large phase II study (ATOMIK study; 484 participants) and in patients with AD, the drug missed the primary end point of change in worst itch NRS from baseline (NCT02975206).”

• cites NCT02975206Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The conclusion that itching results from inflammation may not be generalized to a number of itchy skin disorders such as prurigo nodularis, in which targeting itch remains promising.

“However, this conclusion may not be generalized for a number of itchy skin disorders such as prurigo nodularis in which targeting itch remains promising193,205,210–212.”

• cites [193] Stander, S. et al. Trial of nemolizumab in moderate-to-severe prurigo nodularis. N. Engl. J. Med. 382, 706–716 (2020). Report on the efficacy of the anti-IL-31 biologic nemolizumab in prurigo nodularis. sourceNot checked — no full text of the source
• cites [205] Stander, S. et al. Serlopitant reduced pruritus in patients with prurigo nodularis in a phase 2, randomized, placebo-controlled trial. J. Am. Acad. Dermatol. 80, 1395–1402 (2019). sourceNot checked — no full text of the source
• cites [210] Stander, S., Spellman, M. C., Kwon, P. & Yosipovitch, G. The NK1 receptor antagonist serlopitant for treatment of chronic pruritus. Expert Opin. Investig. Drugs 28, 659–666 (2019). sourceNot checked — no full text of the source

In a pooled safety analysis of cumulative data from eight studies with 2,531 patients, there were no signals for serious or opportunistic infections with baricitinib.

“In a pooled safety analysis of the cumulative data from eight studies with 2,531 patients (2,247 patient-years with median duration of 310 days) there were no signals for serious or opportunistic infections236.”

• cites [236] Bieber, T. et al. Pooled safety analysis of baricitinib in adult patients with atopic dermatitis from 8 randomized clinical trials. J. Eur. Acad. Dermatol. Venereol. 35, 476–485 (2020). sourceNot checked — no full text of the source

Serlopitant, an NK1R antagonist, has shown efficacy in reducing pruritus in a phase II study in patients with treatment-refractory prurigo nodularis.

“Serlopitant is a NK1R antagonist that has shown efficacy in reducing pruritus in a phase II study in patients with treatment-refractory prurigo nodularis205.”

• cites [205] Stander, S. et al. Serlopitant reduced pruritus in patients with prurigo nodularis in a phase 2, randomized, placebo-controlled trial. J. Am. Acad. Dermatol. 80, 1395–1402 (2019). sourceNot checked — no full text of the source

As a common feature of all JAK inhibitors, there was a rapid (within 36 hours) and sustained reduction in the itch sensation.

“As a common feature of all JAKi, there was a rapid (within 36 h) and sustained reduction in the itch sensation.”

Because receptors for TH2 and TH22 cytokines involve downstream JAK-STAT signalling, JAK inhibitors represent interesting compounds for the therapy of atopic dermatitis.

“As the receptors for TH2 and TH22 cytokines involve downstream JAK–STAT signalling, JAKi represent interesting compounds for the therapy of AD.”

The substance P/NK1R signalling pathway could be pharmacologically targeted to control itching sensation and neurogenic inflammation.

“suggesting that this signalling pathway could be pharmacologically targeted to control itching sensation and neurogenic inflammation203,204.”

• cites [203] Stander, S. & Luger, T. A. NK-1 antagonists and itch. Handb. Exp. Pharmacol. 226, 237–255 (2015). sourceNot checked — no full text of the source
• cites [204] Zeidler, C. & Stander, S. The pathogenesis of prurigo nodularis–‘super-itch’ in exploration. Eur. J. Pain. 20, 37–40 (2016). sourceNot checked — no full text of the source

Simultaneous targeting of JAKs and SYK by cerdulatinib appears to be an appealing strategy for topical pharmacological intervention in atopic dermatitis.

“Therefore, simultaneous targeting of JAKs and SYK by cerdulatinib appears to be an appealing strategy for topical pharmacological intervention in AD.”

Overexpression of substance P and NK1R induces itching skin disorders including atopic dermatitis.

“Overexpression of substance P and NK1R induces itching skin disorders including AD199–202”

• cites [199] Pincelli, C. et al. Neuropeptides in skin from patients with atopic dermatitis: an immunohistochemical study. Br. J. Dermatol. 122, 745–750 (1990). sourceNot checked — no full text of the source
• cites [200] Tobin, D. et al. Increased number of immunoreactive nerve fibers in atopic dermatitis. J. Allergy Clin. Immunol. 90, 613–622 (1992). sourceNot checked — no full text of the source
• cites [201] Jarvikallio, A., Harvima, I. T. & Naukkarinen, A. Mast cells, nerves and neuropeptides in atopic dermatitis and nummular eczema. Arch. Dermatol. Res. 295, 2–7 (2003). sourceNot checked — no full text of the source

Unlike selective JAK inhibitors, there was no increase in acne under baricitinib.

“Interestingly, unlike selective JAKi (see below), there was no increase in acne under baricitinib.”

• cites [236] Bieber, T. et al. Pooled safety analysis of baricitinib in adult patients with atopic dermatitis from 8 randomized clinical trials. J. Eur. Acad. Dermatol. Venereol. 35, 476–485 (2020). sourceNot checked — no full text of the source

In the BREEZE-AD2 study, baricitinib achieved IGA 0/1 in 14% of patients versus 5% in the placebo group.

“and 14% versus 5% in the placebo group (BREEZE-AD2 study)235.”

• cites [235] Simpson, E. L. et al. Baricitinib in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: results from two randomised monotherapy phase 3 trials. Br. J. Dermatol. 183, 242–255 (2020). sourceNot checked — no full text of the source

Translational efforts to convert this knowledge into drug discovery have paved the way for an impressive number of preclinical and clinical development programmes.

“Translational efforts to convert this knowledge into drug discovery have paved the way for an impressive number of preclinical and clinical development programmes.”

Multiple factors contribute to the high heterogeneity of age of disease onset, variations in clinical phenotype (particularly in different ethnic backgrounds) and different risks for early development of an atopic march with atopic comorbidities, neuropsychiatric comorbidities or later non-atopic comorbidities.

“There are multiple factors that contribute to the high heterogeneity of the age of disease onset in patients with AD, the variations in the clinical phenotype (particularly in different ethnic backgrounds) and the different risks for early development of an ‘atopic march’ with atopic comorbidities (that is, allergic rhinitis and asthma), neuropsychiatric comorbidities (anxiety, depression) or”

These factors, including diverse environmental influences, a complex genotype, microbiome-derived signals and a dynamic immune response, also underlie the highly variable therapeutic response and adverse events to established and new compounds for atopic dermatitis therapy.

“These factors, which include diverse environmental influences, a complex genotype, microbiome-derived signals and a dynamic immune response, also underlie the highly variable therapeutic response and adverse events to established and new compounds for AD therapy243.”

• cites [243] Agnihotri, G. & Lio, P. A. Revisiting therapies for atopic dermatitis that failed clinical trials. Clin. Drug Investig. 40, 421–431 (2020). sourceNot checked — no full text of the source

JAK inhibitors are not the 'one-size-fits-all' approach for atopic dermatitis, as is the case for rheumatoid arthritis.

“Clearly, as for rheumatoid arthritis, JAKi are not the ‘one-size-fits-all’ approach for AD.”

Phase III trials with these compounds have highlighted the variability of clinical response.

“However, although patients expect that such new compounds provide full clinical response in a monotherapy regimen, the phase III trials with these compounds have highlighted the variability of the clinical response.”

For baricitinib, identification of the good-responder population is an unmet need.

“This is certainly the case for the JAK1/JAK2 inhibitor baricitinib, for which the identification of the good-responder population is an unmet need.”

In an animal model of atopic dermatitis, HY209 reduced TH2 inflammation via inhibition of nuclear factor κB and p38 kinase.

“In an animal model of AD, HY209 reduced TH2 inflammation via inhibition of nuclear factor κB (NF-κB) and p38 kinase.”

• cites [240] Ghaderpour, A., Kim, Y.-H., Lee, H.-C. & Seong, S.-Y. HY209 ameliorates atopic dermatitis through NF-KB and P38 inhibition. J. Immunol. 204 (Suppl. 1), 147.37 (2020). sourceNot checked — no full text of the source

Phase III data of the dual JAK1/JAK2 inhibitor baricitinib suggest lower efficacy than the more JAK1-specific inhibitors abrocitinib and upadacitinib.

“However, the phase III data of the dual JAK1/JAK2 inhibitor baricitinib suggest a lower efficacy than the more JAK1-specific inhibitors abrocitinib and upadacitinib.”

Early precise determination of the genetic and/or environmental risk factors leading to the emergence of atopic dermatitis in infancy, as well as the risk of developing an atopic march, bears the potential of a disease-modifying prevention strategy early in life.

“An early precise determination of the genetic and/or environmental risk factors leading to the emergence of AD in infancy as well as the risk of developing an atopic march (that is, atopic comorbidities such as allergic asthma) bears the tremendous potential of a disease-modifying prevention strategy early in life244.”

• cites [244] Bieber, T., Cork, M. & Reitamo, S. Atopic dermatitis: a candidate for disease-modifying strategy. Allergy 67, 969–975 (2012). sourceNot checked — no full text of the source

VTP-38543 did not significantly downregulate markers of inflammation.

“However, the compound did not significantly downregulate markers of inflammation.”

• cites NCT02655679Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Consequently, there is now an expanding pipeline for the therapy of atopic dermatitis.

“Consequently, there is now an expanding pipeline for the therapy of this complex disorder.”

Another approach to affect inflammation is to inhibit tropomyosin receptor kinases, which bind neurotrophins known to aggravate skin inflammation.

“Another approach to affect inflammation is to inhibit the tropomyosin receptor kinases (TRKs), which bind neurotrophins known to aggravate skin inflammation239.”

• cites [239] Peters, E. M. et al. Nerve growth factor partially recovers inflamed skin from stress-induced worsening in allergic inflammation. J. Invest. Dermatol. 131, 735–743 (2011). sourceNot checked — no full text of the source

The effects observed with VTP-38543 were not dose-dependent.

“Moreover, the effects observed were not dose-dependent (NCT02655679).”

• cites NCT02655679Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The steadily increasing number of new drugs in development for atopic dermatitis indicates the potential for precision medicine to generate an optimized benefit-risk ratio, particularly in paediatric and elderly patients.

“The steadily increasing number of new drugs in development for AD has indicated the potential for precision medicine to generate an optimized benefit–risk ratio, particularly in age ranges where safety issues are of crucial interest such as in paediatric patients, as well as in the elderly, where drug–drug interactions represent another potential threat.”