Atopic dermatitis: an expanding therapeutic pipeline for a complex disease

In the paper

“The skin microbiome is regulated on one hand by the quorum-sensing mechanisms between bacterial strains26 and on the other hand by the crosstalk between the bacteria and the skin innate immune system and epidermal Langerhans cells continuously educating the adaptive immune system.”

What the sources say

• Supported

  Citation 26 is attached to the quorum-sensing clause, not the subsequent claim about immune-system crosstalk. The Introduction and Discussion report that autoinducing peptides from some skin commensal staphylococcal strains repress S. aureus quorum-sensing activity, demonstrating regulation between bacterial strains on the skin. (LLM, conf=0.92)

  cites [26] Williams, M. R. et al. Quorum sensing between bacterial species on the skin protects against epidermal injury in atopic dermatitis. Sci. Transl Med. 11, eaat8329 (2019). source
• ?Not checked — no full text of the sourcecites [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. source

In the paper

“Skin from patients with AD presents significant differences in the microbiome compared with healthy individuals, in whom Roseomonas mucosa was found to be the most representative Gram-negative bacteria41.”

What the sources say

• Partly supported

  The “AD AND S AUREUS: EPIDEMIOLOGY” section reports reduced microbial diversity during AD flares and greater S aureus carriage than in healthy controls, supporting a difference in skin microbiomes. The “CAN COMMENSAL ORGANISMS BE USED AS THERAPY FOR AD?” section identifies Roseomonas mucosa as Gram-negative, but does not say it is the most representative Gram-negative bacterium in healthy individuals. Page numbers were not available in our copy. (LLM, conf=0.88)

  cites [41] Paller, A. S. et al. The microbiome in patients with atopic dermatitis. J. Allergy Clin. Immunol. 143, 26–35 (2019). sourceExperimental — accuracy not yet measured

In the paper

“T helper 2 (TH2) immune polarization is accompanied by IgE sensitization to environmental allergens and self proteins and has a key role in atopic disorders101,257.”

What the sources say

• Partly supported

  The Figure 3 caption (Clinical and research implications; page unavailable) describes a proposed mechanism in atopic dermatitis in which a TH2 response accompanies IgE directed against self-proteins. The paper also discusses IgE responses to environmental allergens, but its Abstract says the role of autoreactivity is unclear and reports no IgE autoreactivity in subjects with allergic rhinoconjunctivitis. It therefore does not establish the claimed key role of this combined sensitization across atopic disorders. (LLM, conf=0.88)

  cites [101] Tang, T. S., Bieber, T. & Williams, H. C. Does “autoreactivity” play a role in atopic dermatitis? J. Allergy Clin. Immunol. 129, 1209–1215 (2012). Review paper analysing the evidence for autoimmunity in AD. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [257] Valenta, R. et al. Immunoglobulin E response to human proteins in atopic patients. J. Invest. Dermatol. 107, 203–208 (1996). source

In the paper

“After initial promising results using such emollients and moisturizers in the prevention of AD in newborns at high risk48,49, a more recent report has questioned this strategy50,51.”

What the sources say

• Supported

  The Methods describe a trial of emollient use from birth in neonates at high risk of atopic dermatitis. The Results report a lower incidence at six months in the emollient group (22% versus 43% in controls), supporting the cited description of initial promising results. The later report questioning the strategy is attributed to citations 50 and 51, not this source. (LLM, conf=0.94)

  cites [48] Simpson, E. L. et al. Emollient enhancement of the skin barrier from birth offers effective atopic dermatitis prevention. J. Allergy Clin. Immunol. 134, 818–823 (2014). source
• ?Not checked — no full text of the sourcecites [49] Horimukai, K. et al. Application of moisturizer to neonates prevents development of atopic dermatitis. J. Allergy Clin. Immunol. 134, 824–830 (2014). Together with Simpson et al. (2014), first reported on the putative preventive value of simple skin care in newborns at risk of developing AD. source
• Supported

  The paper describes promising signals from small pilot studies (p. 1), then reports that a larger trial in high-risk newborns found no preventive effect (p. 1). It concludes that emollients should not currently be recommended for primary prevention of atopic dermatitis in infants (p. 2), directly supporting the claim that a more recent report questioned the strategy. (LLM, conf=0.94)

  cites [50] Perrett, K. P. & Peters, R. L. Emollients for prevention of atopic dermatitis in infancy. Lancet 395, 923–924 (2020). source
• ?Not checked — no full text of the sourcecites [51] Skjerven, H. O. et al. Skin emollient and early complementary feeding to prevent infant atopic dermatitis (PreventADALL): a factorial, multicentre, cluster-randomised trial. Lancet 395, 951–961 (2020). source

In the paper

“The role of the innate immune system in the early phase of AD was demonstrated using animal models52–54 and is likely of clinical relevance in infancy55.”

What the sources say

• Supported

  Citation 55 is attached to the claim of likely clinical relevance in infancy. The Discussion says the epithelial mechanism identified in this study could explain why eczematous lesions in infants often begin before specific IgE antibodies appear. That supports the citing sentence’s hedged claim; the animal-model clause is attributed to citations 52–54. (LLM, conf=0.88)

  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). source
• Partly supported

  The Results section on cutaneous inflammation shows that filaggrin-deficient mice develop dermatitis without adaptive immunity, and the Discussion reports increased skin ILC2s in patients with atopic dermatitis and filaggrin mutations. The paper also describes atopic dermatitis as an early-life condition, but it does not establish that the innate-immune finding applies specifically to infants; clinical relevance in infancy remains an extrapolation. (LLM, conf=0.82)

  cites [53] Saunders, S. P. et al. Spontaneous atopic dermatitis is mediated by innate immunity, with the secondary lung inflammation of the atopic march requiring adaptive immunity. J. Allergy Clin. Immunol. 137, 482–491 (2016). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [54] Chieosilapatham, P. et al. Keratinocytes: innate immune cells in atopic dermatitis. Clin. Exp. Immunol. 204, 296–309 (2021). source
• Partly supported

  The Introduction says atopic dermatitis often begins in infancy, and section 6.1 reports an epithelial-derived cytokine in human atopic-dermatitis lesions and its role in mouse models of skin inflammation. These passages make clinical relevance in infancy plausible, but the copy does not establish the role of innate immunity specifically in the early phase of infant atopic dermatitis. The animal-model demonstration is attached to other citations in the citing sentence. (LLM, conf=0.79)

  cites [55] Han, H., Roan, F. & Ziegler, S. F. The atopic march: current insights into skin barrier dysfunction and epithelial cell-derived cytokines. Immunol. Rev. 278, 116–130 (2017). sourceExperimental — accuracy not yet measured

In the paper

“The itch-scratching reflex contributes to further disruption of the epidermal barrier function, keratinocyte damage and activation of local dendritic cells, which in turn will further activate the adaptive immune response and subsequent inflammatory reaction29,181,182.”

What the sources say

• ?Not checked — no full text of the sourcecites [29] Mack, M. R. & Kim, B. S. The itch-scratch cycle: a neuroimmune perspective. Trends Immunol. 39, 980–991 (2018). source
• ?Not checked — no full text of the sourcecites [181] Erickson, S., Heul, A. V. & Kim, B. S. New and emerging treatments for inflammatory itch. Ann. Allergy Asthma Immunol. 126, 13–20 (2021). source
• Partly supported

  The Prurigo Nodularis section (page not available) says itch is believed to drive rash development and describes chronic scratching, supporting a general link between itch and skin lesions. The Atopic Dermatitis section discusses barrier-derived cytokines and immune inflammation, but the copy does not establish that scratching damages keratinocytes or activates dendritic cells, which then amplify the adaptive immune response. (LLM, conf=0.74)

  cites [182] Yang, T. B. & Kim, B. S. Pruritus in allergy and immunology. J. Allergy Clin. Immunol. 144, 353–360 (2019). sourceExperimental — accuracy not yet measured

In the paper

“So far, however, AD has primarily been considered as merely a skin disorder in which local anti-inflammatory therapy of the disease flares should be the first-line approach14,15.”

What the sources say

• ?Could not verify

  The available passage, under “Crisaborole ointment is not recommended for treatment of AD in pregnant women” (page unavailable), discusses medication safety during pregnancy and lactation. Searches for local anti-inflammatory treatment of flares and first-line topical therapy found no passage addressing whether AD has primarily been regarded as a skin disorder or whether such therapy should be first-line. (LLM, conf=0.73)

  cites [14] Vestergaard, C., Wollenberg, A. & Thyssen, J. P. European Task Force on Atopic Dermatitis (ETFAD) Position Paper: treatment of parental atopic dermatitis during preconception, pregnancy and lactation period. J. Eur. Acad. Dermatol. Venereol. 34, 426–427 (2020). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [15] Thyssen, J. P. et al. European Task Force on Atopic Dermatitis (ETFAD): treatment targets and treatable traits in atopic dermatitis. J. Eur. Acad. Dermatol. Venereol. 34, e839–e842 (2020). source

In the paper

“The Harmonising Outcome Measures for Eczema (HOME) initiative has established a core outcome set of tools and end points to be used in clinical trials258–261 and are discussed in detail elsewhere37.”

What the sources say

• Partly supported

  Step 2 identifies four core outcome domains for atopic eczema trials, and Step 3 reports that HOME selected EASI to measure clinical signs. But Step 3 says instruments for the other domains had not yet been agreed on, so the paper does not support the claim that a full set of tools had been established. Page numbers are unavailable in our copy. (LLM, conf=0.90)

  cites [258] Schmitt, J. et al. The Harmonising Outcome Measures for Eczema (HOME) statement to assess clinical signs of atopic eczema in trials. J. Allergy Clin. Immunol. 134, 800–807 (2014). sourceExperimental — accuracy not yet measured
• Partly supported

  The paper identifies four core outcome domains for atopic eczema trials and reports recommended instruments for clinician-reported signs and patient-reported symptoms (DOI section). But it says preferred instruments for quality of life and long-term control still require further work, so it does not support the implication that a complete set of tools had been established. (LLM, conf=0.88)

  cites [259] Chalmers, J. R. et al. Report from the fourth international consensus meeting to harmonize core outcome measures for atopic eczema/dermatitis clinical trials (HOME initiative). Br. J. Dermatol. 175, 69–79 (2016). sourceExperimental — accuracy not yet measured
• Partly supported

  The References section cites HOME consensus work on core outcome measures for atopic dermatitis trials, supporting HOME’s role in harmonising trial outcomes. But the Clinical and research implications section says that how to measure long-term control remained a HOME research priority, and the paper does not say that a complete core set of tools and end points had been established. Page numbers are not available in our copy. (LLM, conf=0.83)

  cites [260] Langan, S. M. et al. Measuring long-term disease control in patients with atopic dermatitis: a validation study of well-controlled weeks. J. Allergy Clin. Immunol. 140, 1580–1586 (2017). sourceExperimental — accuracy not yet measured
• Supported

  The paper’s clinical implications section identifies four HOME core domains for atopic eczema trials and names recommended instruments for signs and symptoms. Its conclusion states that the core outcome set is complete and that the specified domains and instruments should be used in new clinical trials. Page numbers are unavailable in our copy. (LLM, conf=0.94)

  cites [261] Thomas, K. S. et al. Recommended core outcome instruments for health-related quality of life, long-term control and itch intensity in atopic eczema trials: results of the HOME VII consensus meeting. Br. J. Dermatol. https://doi.org/10.1111/bjd.19673 (2021). source

In the paper

“Therefore, individually and empirically adapted skin care using emollients or moisturizers to complement the control of inflammation still remains the only approach to improve barrier function, dryness and water loss and is qualified as basis therapy35.”

What the sources say

• Partly supported

  The Emollient therapy section (p. 7) recommends daily emollients and explains that their ingredients hydrate the skin and reduce evaporation; it also advises treating acute inflammation with anti-inflammatory topicals first. The paper places skincare under basic therapy (p. 5), but does not say that individually adapted emollient care is the only approach to improving barrier function, dryness, and water loss. (LLM, conf=0.86)

  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). sourceExperimental — accuracy not yet measured

In the paper

“Tapinarof (also known as benvitimod) is a natural AhR agonist60 that significantly reduces inflammatory responses both in animal models and in human skin when used topically.”

What the sources say

• Supported

  The opening summary (p. 1) identifies tapinarof as a naturally derived topical treatment and AhR agonist. It reports reduced inflammatory measures after topical treatment in mice and moderated proinflammatory cytokine expression in ex vivo human skin; the Th17 cytokine section (p. 5) reports approximately 50% inhibition of IL17A expression in a human-skin model. (LLM, conf=0.91)

  cites [60] Smith, S. H. et al. Tapinarof Is a natural AhR agonist that resolves skin inflammation in mice and humans. J. Invest. Dermatol. 137, 2110–2119 (2017). source

In the paper

“IL-1α is a proinflammatory cytokine released by keratinocytes after injury and by skin dysbiosis69.”

What the sources say

• Supported

  The Discussion states that keratinocytes release intracellular IL-1α following skin injury and dysbiosis, and that the released IL-1α drives skin inflammation. The Results also report increased IL-1α release from mechanically injured keratinocytes. (LLM, conf=0.94)

  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). source

In the paper

“It is approved for AD in many countries and real-world data support the efficacy reported in the phase III programme in adults83–86.”

What the sources say

• Partly supported

  The Discussion reports that this real-life adult AD study found effectiveness similar to that observed in clinical trials, supporting the efficacy comparison. The Introduction calls dupilumab available for adult AD, but the cited passages do not establish approval in many countries. (LLM, conf=0.85)

  cites [83] Faiz, S. et al. Effectiveness and safety of dupilumab for the treatment of atopic dermatitis in a real-life French multicenter adult cohort. J. Am. Acad. Dermatol. 81, 143–151 (2019). sourceExperimental — accuracy not yet measured
• Partly supported

  The Abstract reports real-world results in adults with atopic eczema and concludes that they show no major efficacy–effectiveness gap, largely confirming trial data. It says dupilumab was launched in Germany, but does not establish approval for AD in many countries. (LLM, conf=0.87)

  cites [84] Abraham, S. et al. Implementation of dupilumab in routine care of atopic eczema. Results from the German national registry TREATgermany. Br. J. Dermatol. 183, 382–384 (2020). sourceExperimental — accuracy not yet measured
• Partly supported

  The introductory passage (page unavailable) reports dupilumab approvals for AD in the United States, Japan, and Europe and describes efficacy in phase 1–3 trials. The Methods and Discussion (pages unavailable) identify this paper as a clinical-trial open-label extension, not real-world data; it therefore does not support the real-world-data part of the claim. (LLM, conf=0.88)

  cites [85] Deleuran, M. et al. Dupilumab shows long-term safety and efficacy in patients with moderate to severe atopic dermatitis enrolled in a phase 3 open-label extension study. J. Am. Acad. Dermatol. 82, 377–388 (2020). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [86] Wang, C., Kraus, C. N., Patel, K. G., Ganesan, A. K. & Grando, S. A. Real-world experience of dupilumab treatment for atopic dermatitis in adults: a retrospective analysis of patients’ records. Int. J. Dermatol. 59, 253–256 (2020). source

In the paper

“Therefore, the anti-IL-36R antibody spesolimab, which has been successfully tested in a rare form of pustular psoriasis74, has been explored for AD in a phase IIa study with 51 patients, the results of which are expected by the end of 2021.”

What the sources say

• Supported

  The citation is attached to the claim that the anti-IL-36-receptor antibody was tested in a rare form of pustular psoriasis, not to the later statement about the atopic-dermatitis study. The opening passage (p. 1) describes a seven-patient proof-of-concept study in generalized pustular psoriasis, and the results (p. 1) report clear or almost clear skin in all seven by week 4. The authors caution that further investigation is needed to establish clinical efficacy (p. 3). (LLM, conf=0.91)

  cites [74] Bachelez, H. et al. Inhibition of the interleukin-36 pathway for the treatment of generalized pustular psoriasis. N. Engl. J. Med. 380, 981–983 (2019). source

In the paper

“In a proof-of-concept study with a single application of the anti-IL-33 antibody etokimab (ANB020) in 12 patients with moderate or severe AD, 33% of patients reached the primary end point EASI75 and 83% reached EASI50 (ref.68).”

What the sources say

• Partly supported

  The Study design section describes a single dose of etokimab in 12 adults with moderate-to-severe atopic dermatitis, and Efficacy reports 33% reaching EASI75 and 83.3% reaching EASI50 at day 29. The citing sentence also calls EASI75 the primary endpoint, but Study design lists EASI scores among the main clinical endpoints and does not identify EASI75 as the primary endpoint. Page numbers were not available in our copy. (LLM, conf=0.86)

  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). sourceExperimental — accuracy not yet measured

In the paper

“In the pivotal studies with dupilumab, 11% of the patients developed eye disorders (for example, conjunctivitis, keratoconjunctivitis and keratitis); this adverse event of special interest (AESI) has been attributed to its IL-13 blocking activity93.”

What the sources say

• Partly supported

  The Incidence of conjunctivitis section reports increased conjunctivitis in dupilumab-treated patients with atopic dermatitis, but rates varied by trial (8.6%, 17.9%, and 22.1%); it does not report 11% of dupilumab patients developing eye disorders. The Discussion (page unavailable in our copy) lists reduced IL-13-related mucus production among several proposed mechanisms and says the exact pathogenesis is unknown, so it does not establish IL-13 blockade as the cause. (LLM, conf=0.88)

  cites [93] Akinlade, B. et al. Conjunctivitis in dupilumab clinical trials. Br. J. Dermatol. 181, 459–473 (2019). sourceExperimental — accuracy not yet measured

In the paper

“Higher rates were described in long-term studies and in real-world reports83–86 but interestingly not in asthma94.”

What the sources say

• Supported

  This source is a real-world report: the Discussion says its adult atopic-dermatitis cohort had a particularly high rate of conjunctivitis with dupilumab (38.2% versus 8% in a trial meta-analysis). It also notes that conjunctivitis was not observed in the asthma trials it discusses. The citing sentence assigns long-term studies and asthma to other citations; this source supports the real-world portion. (LLM, conf=0.93)

  cites [83] Faiz, S. et al. Effectiveness and safety of dupilumab for the treatment of atopic dermatitis in a real-life French multicenter adult cohort. J. Am. Acad. Dermatol. 81, 143–151 (2019). source
• Supported

  The Abstract reports conjunctivitis in 13.3% of dupilumab-treated registry patients at three months and 23% at six months, and notes higher rates in other routine-care cohorts. This supports the real-world-report portion attributed to this paper. The asthma comparison is attached to citation 94, not to this source. (LLM, conf=0.87)

  cites [84] Abraham, S. et al. Implementation of dupilumab in routine care of atopic eczema. Results from the German national registry TREATgermany. Br. J. Dermatol. 183, 382–384 (2020). source
• Supported

  The Safety section reports conjunctivitis in 10.7% of patients during the long-term dupilumab extension study. The Discussion says these rates were comparable to earlier atopic dermatitis trials, in which conjunctivitis occurred more frequently with dupilumab than placebo. This source supports the long-term-study portion of the citing sentence; separate citations are attached to the real-world and asthma portions. (LLM, conf=0.89)

  cites [85] Deleuran, M. et al. Dupilumab shows long-term safety and efficacy in patients with moderate to severe atopic dermatitis enrolled in a phase 3 open-label extension study. J. Am. Acad. Dermatol. 82, 377–388 (2020). source
• ?Not checked — no full text of the sourcecites [86] Wang, C., Kraus, C. N., Patel, K. G., Ganesan, A. K. & Grando, S. A. Real-world experience of dupilumab treatment for atopic dermatitis in adults: a retrospective analysis of patients’ records. Int. J. Dermatol. 59, 253–256 (2020). source
• Supported

  The citation is attached to the asthma comparison, not the preceding claim about long-term and real-world reports. The Discussion says conjunctivitis rates in the adolescent asthma trial were similar for dupilumab- and placebo-treated patients; the Results report no difference between groups in adolescents or adults. (LLM, conf=0.93)

  cites [94] Bansal, A. et al. Conjunctivitis in dupilumab clinical trials for adolescents with atopic dermatitis or asthma. Am. J. Clin. Dermatol. 22, 101–115 (2021). source

In the paper

“In keratinocytes, IL-22 exerts multiple biological activities, including their proliferation and downregulation of filaggrin expression120,121.”

What the sources say

• ?Not checked — no full text of the sourcecites [120] Gutowska-Owsiak, D., Schaupp, A. L., Salimi, M., Taylor, S. & Ogg, G. S. Interleukin-22 downregulates filaggrin expression and affects expression of profilaggrin processing enzymes. Br. J. Dermatol. 165, 492–498 (2011). source
• Partly supported

  The Introduction (page unavailable) states that IL-22 promotes keratinocyte proliferation and inhibits differentiation. It does not specifically state that IL-22 downregulates filaggrin expression; searches for filaggrin and FLG found no such passage in our copy. (LLM, conf=0.86)

  cites [121] Eyerich, S. et al. Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling. J. Clin. Invest. 119, 3573–3585 (2009). sourceExperimental — accuracy not yet measured

In the paper

“Circulating IL-22 correlates with the severity of AD and appears as a key driver in the inflammatory reaction116,119.”

What the sources say

• Partly supported

  The Results (page unavailable) correlate the frequency of IL-22-producing CD8+ T cells in AD lesions—not circulating IL-22—with disease severity. The Discussion (page unavailable) suggests an IL-22 contribution to skin changes, but does not establish it as a key driver of the inflammatory reaction. (LLM, conf=0.88)

  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). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section on acute AD reports a positive correlation between lesional IL-22 mRNA and severity (SCORAD), but it was not statistically significant (r=0.55, P=0.132); it does not measure circulating IL-22. The Discussion proposes that IL-22 may contribute to epidermal changes, rather than establishing it as a key driver of inflammation. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  cites [119] Gittler, J. K. et al. Progressive activation of T(H)2/T(H)22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis. J. Allergy Clin. Immunol. 130, 1344–1354 (2012). sourceExperimental — accuracy not yet measured

In the paper

“A significant part of the sensitization process leading to the generation of IgE responses against environmental allergens (including food allergens)100 as well as against self proteins101 correlates with cutaneous inflammation and overall severity102,103.”

What the sources say

• Supported

  Citation 100 is attached to environmental allergens, including food allergens, rather than to self proteins or overall AD severity, which have separate citations. In “Data suggesting cutaneous sensitization” (page not supplied), the paper describes food proteins crossing a disrupted skin barrier and leading to IgE production, and links early severe eczema with subsequent food allergy. (LLM, conf=0.90)

  cites [100] Lack, G. Update on risk factors for food allergy. J. Allergy Clin. Immunol. 129, 1187–1197 (2012). source
• Partly supported

  The ‘How common is autoreactivity in patients with AD?’ section reports correlations between autoreactivity and AD severity, although only two of five analyses found statistically significant correlations. The paper’s discussion of self-protein sensitization also links it to skin inflammation. It does not establish the same severity correlation for IgE responses to environmental allergens; the Abstract says their role in AD persistence is unclear. Page numbers are unavailable in our copy. (LLM, conf=0.85)

  cites [101] Tang, T. S., Bieber, T. & Williams, H. C. Does “autoreactivity” play a role in atopic dermatitis? J. Allergy Clin. Immunol. 129, 1209–1215 (2012). Review paper analysing the evidence for autoimmunity in AD. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [102] Laske, N. & Niggemann, B. Does the severity of atopic dermatitis correlate with serum IgE levels? Pediatr. Allergy Immunol. 15, 86–88 (2004). source
• Partly supported

  The Results (page unavailable) report that total IgE levels correlated with AD severity measured by SCORAD in extrinsic AD, but not intrinsic AD. The Discussion (page unavailable) considers a possible effect of IgE on skin inflammation; it does not establish that effect or show that IgE responses to environmental allergens or self proteins correlate with inflammation or severity. (LLM, conf=0.88)

  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). sourceExperimental — accuracy not yet measured

In the paper

“T cells are recruited by locally produced chemotactic mediators, and inhibition of their migration represents an appealing strategy18,54,149,150.”

What the sources say

• ?Not checked — no full text of the sourcecites [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. source
• ?Not checked — no full text of the sourcecites [54] Chieosilapatham, P. et al. Keratinocytes: innate immune cells in atopic dermatitis. Clin. Exp. Immunol. 204, 296–309 (2021). source
• Supported

  The paper reports that chemokines produced by bronchial cells precede the recruitment of Th2 cells (Abstract; page not supplied). Its therapeutic-strategies section describes chemokine receptor antagonists as a treatment approach, while noting that few have become effective treatments. (LLM, conf=0.90)

  cites [149] Castan, L., Magnan, A. & Bouchaud, G. Chemokine receptors in allergic diseases. Allergy 72, 682–690 (2017). source
• ?Not checked — no full text of the sourcecites [150] Abboud, D. & Hanson, J. Chemokine neutralization as an innovative therapeutic strategy for atopic dermatitis. Drug Discov. Today 22, 702–711 (2017). source

In the paper

“These mediators are produced in high amounts in AD and correlate with the severity of AD156,157.”

What the sources say

• ?Not checked — no full text of the sourcecites [156] Kataoka, Y. Thymus and activation-regulated chemokine as a clinical biomarker in atopic dermatitis. J. Dermatol. 41, 221–229 (2014). source
• Supported

  The ‘Biomarkers correlating with clinical severity’ section identifies several TH2-related chemokines whose levels correlate with AD severity, and Table II describes CCL27 as upregulated in AD. The review qualifies that circulating biomarkers are found in moderate-to-severe AD but may not be consistently elevated in mild AD. (LLM, conf=0.86)

  cites [157] Renert-Yuval, Y. et al. Biomarkers in atopic dermatitis-a review on behalf of the International Eczema Council. J. Allergy Clin. Immunol. 147, 1174–1190 (2021). State of the art review paper in the field of biomarker discovery in AD. source

In the paper

“a phase II RCT in AD showed a significant improvement only for the high dose compared with placebo (32% reduction in EASI score versus 11% in the placebo group), but the study was discontinued owing to adverse events131.”

What the sources say

• Partly supported

  The Clinical efficacy passage reports a 31.6% EASI reduction with apremilast 40 mg twice daily versus 11.0% with placebo at week 12; the 30 mg dose did not reach statistical significance. The Safety section says adverse events, including cellulitis, led to discontinuation of the 40 mg treatment arm—not the study as a whole. (LLM, conf=0.90)

  cites [131] Simpson, E. L. et al. A phase 2 randomized trial of apremilast in patients with atopic dermatitis. J. Invest. Dermatol. 139, 1063–1072 (2019). sourceExperimental — accuracy not yet measured

In the paper

“up to 40% of patients reached the stringent clinical efficacy end point IGA 0/1, in contrast to only 8% in the placebo group, along with a greater decrease in the other secondary end points (EASI, visual analogue scale pruritus and Patient-Oriented Eczema Measure (POEM)) compared with placebo.”

What the sources say

• Supported

  The Results (Efficacy) report week-4 IGA success of 40.00% in the 1% difamilast group and 8.33% in the vehicle group. The Discussion reports greater improvements in EASI, VAS pruritus and POEM with both difamilast concentrations than with vehicle. The Methods define IGA success as a score of 0 or 1 with at least a two-grade reduction from baseline. (LLM, conf=0.94)

  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). source

In the paper

“IL-31 is a prominent pruritogenic cytokine produced by infiltrating TH2 cells in AD and correlates with disease severity97,184,185.”

What the sources say

• ?Not checked — no full text of the sourcecites [97] Byeon, J. H. et al. Correlation of serum interleukin-31 with pruritus and blood eosinophil markers in children with atopic dermatitis. Allergy Asthma Proc. 41, 59–65 (2020). source
• Supported

  Section 2 identifies activated TH2 cells and skin-homing T cells as sources of IL-31. Section 5 reports elevated IL-31 expression in atopic dermatitis lesions and states that serum IL-31 levels correlate with disease severity in children and adults. The Conclusion describes IL-31 as important in atopic itch; page numbers were not available in our copy. (LLM, conf=0.90)

  cites [184] Furue, M., Yamamura, K., Kido-Nakahara, M., Nakahara, T. & Fukui, Y. Emerging role of interleukin-31 and interleukin-31 receptor in pruritus in atopic dermatitis. Allergy 73, 29–36 (2018). source
• Partly supported

  In “Correlation of IL-31 serum levels with severity of atopic dermatitis” (page not provided), the authors report that serum IL-31 correlates with AD severity and describe evidence for a role in pruritus. They identify skin-infiltrating T cells as possible sources and report that IL31 mRNA correlates with TH2 cytokines, but do not establish that infiltrating TH2 cells produce IL-31 in AD skin. (LLM, conf=0.85)

  cites [185] Raap, U. et al. Correlation of IL-31 serum levels with severity of atopic dermatitis. J. Allergy Clin. Immunol. 122, 421–423 (2008). sourceExperimental — accuracy not yet measured

In the paper

“Whereas DCs express S1PR1, S1PR3 and S1PR4, T cells display S1PR1 and S1PR4 (refs164–166)”

What the sources say

• ?Not checked — no full text of the sourcecites [164] Bock, S., Pfalzgraff, A. & Weindl, G. Sphingosine 1-phospate differentially modulates maturation and function of human Langerhans-like cells. J. Dermatol. Sci. 82, 9–17 (2016). source
• Partly supported

  The Results section says the murine Langerhans-cell line XS52 expresses S1P1–S1P4, supporting S1PR1, S1PR3 and S1PR4 in that DC model, but not establishing this as a general DC expression profile. The Introduction discusses S1P signaling in T-cell movement, but does not say T cells express both S1PR1 and S1PR4. (LLM, conf=0.85)

  cites [165] Japtok, L. et al. Sphingosine 1-phosphate modulates antigen capture by murine Langerhans cells via the S1P2 receptor subtype. PLoS ONE 7, e49427 (2012). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [166] Blaho, V. A. & Hla, T. An update on the biology of sphingosine 1-phosphate receptors. J. Lipid Res. 55, 1596–1608 (2014). source

In the paper

“The mechanisms that underlie itching sensation are complex, involving multiple mediators that initiate the activation of peripheral sensory neurons. They offer a number of potential targets for pharmacological intervention29,180–182.”

What the sources say

• ?Not checked — no full text of the sourcecites [29] Mack, M. R. & Kim, B. S. The itch-scratch cycle: a neuroimmune perspective. Trends Immunol. 39, 980–991 (2018). source
• Supported

  The Introduction identifies several itch-related mediators, including histamine, IL-31, IL-4, and IL-13, and reports that IL-4 and IL-13 directly activate sensory neurons. The Introduction and Discussion also identify neuronal IL-4Rα and JAK1 signaling as potential treatment targets for chronic itch. The supplied passages have section labels but no page numbers. (LLM, conf=0.89)

  cites [180] Oetjen, L. K. et al. Sensory neurons co-opt classical immune signaling pathways to mediate chronic Itch. Cell 171, 217–228 (2017). Key paper on how immune mediators interact with sensory neurons to induce itching sensation. source
• ?Not checked — no full text of the sourcecites [181] Erickson, S., Heul, A. V. & Kim, B. S. New and emerging treatments for inflammatory itch. Ann. Allergy Asthma Immunol. 126, 13–20 (2021). source
• Supported

  “Classical Histaminergic Itch and Beyond” describes multiple itch-inducing molecules binding receptors on sensory nerve endings and triggering neuronal activation. The Conclusions describe a complex interplay of molecular signals and identify several targeted therapies under development. (LLM, conf=0.93)

  cites [182] Yang, T. B. & Kim, B. S. Pruritus in allergy and immunology. J. Allergy Clin. Immunol. 144, 353–360 (2019). source

In the paper

“This strategy has been successfully developed with the S1PR1,3–5 agonist fingolimod167 and the S1PR1,5 agonist siponimod168, which are both approved for the therapy of multiple sclerosis.”

What the sources say

• Partly supported

  The “Fingolimod (Gilenya) for Multiple Sclerosis” section states that fingolimod received FDA approval for relapsing MS. The “Next-Generation Lysophospholipid Receptor Modulators and Diseases” section describes siponimod as having entered clinical trials and reports positive phase III results, but does not say it was approved. Page numbers are unavailable in our copy. (LLM, conf=0.90)

  cites [167] Chun, J., Kihara, Y., Jonnalagadda, D. & Blaho, V. A. Fingolimod: lessons learned and new opportunities for treating multiple sclerosis and other disorders. Annu. Rev. Pharmacol. Toxicol. 59, 149–170 (2019). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [168] Gajofatto, A. & Turatti, M. Siponimod to treat secondary progressive multiple sclerosis. Drugs Today 56, 37–46 (2020). source

In the paper

“Thus, the quest for JAK1-selective compounds resulted in the development of second-generation inhibitors such as upadacitinib and abrocitinib17, for which the regulatory approvals are expected before the end of 2021.”

What the sources say

• Partly supported

  The Figure 3 caption identifies upadacitinib as a newer JAK1-targeting inhibitor, and Table 3 lists it in Phase III trials (page numbers unavailable). Our copy does not name abrocitinib or predict regulatory approvals before the end of 2021, so those parts of the attributed claim are unsupported. (LLM, conf=0.84)

  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. sourceExperimental — accuracy not yet measured

In the paper

“Currently, there are more than 90 patented JAKi, many of which are in clinical development for various indications such as rheumatoid arthritis and inflammatory bowel diseases17,215,216.”

What the sources say

• Partly supported

  Table 3 lists JAK inhibitors in clinical trials for rheumatoid arthritis, ulcerative colitis and Crohn’s disease, supporting the clinical-development portion of the claim. The passages from our copy do not establish that more than 90 JAK inhibitors have been patented. (LLM, conf=0.87)

  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. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [215] Schwartz, D. M., Bonelli, M., Gadina, M. & O’Shea, J. J. Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases. Nat. Rev. Rheumatol. 12, 25–36 (2016). Key review on the link between cytokine receptors and the JAK pathways in autoimmune disorders. source
• ?Not checked — no full text of the sourcecites [216] Villarino, A. V., Gadina, M., O’Shea, J. J. & Kanno, Y. SnapShot: Jak-STAT signaling II. Cell 181, 1696–1696 (2020). source

In the paper

“Recently, JAKi were used successfully in treating the cytokine storm generated by the SARS-CoV-2 virus217.”

What the sources say

• Partly supported

  The Background (page unavailable) says small studies reinforced the hypothesis that JAK inhibitors could combat high cytokine expression in SARS-CoV-2 infection. The clinical-outcomes section reports lower mortality and ICU admission among treated COVID-19 patients, but the paper does not establish that JAK inhibitors successfully treated cytokine storm itself. (LLM, conf=0.85)

  cites [217] Walz, L. et al. JAK-inhibitor and type I interferon ability to produce favorable clinical outcomes in COVID-19 patients: a systematic review and meta-analysis. BMC Infect. Dis. 21, 47 (2021). sourceExperimental — accuracy not yet measured

In the paper

“Owing to its particular activity against all JAKs and the spleen tyrosine kinase (SYK), cerdulatinib was initially developed as a systemic therapy for haematological malignancies228.”

What the sources say

• Partly supported

  The Research Paper section describes cerdulatinib as an orally available inhibitor of SYK and JAK kinases, and the Discussion reports a clinical trial in patients with CLL and non-Hodgkin lymphoma (page numbers unavailable). The copy supports its activity and investigation as a systemic treatment for haematological malignancies, but does not establish that it inhibits every JAK family member or that this was its initial development purpose. (LLM, conf=0.84)

  cites [228] Guo, A. et al. Dual SYK/JAK inhibition overcomes ibrutinib resistance in chronic lymphocytic leukemia: cerdulatinib, but not ibrutinib, induces apoptosis of tumor cells protected by the microenvironment. Oncotarget 8, 12953–12967 (2017). sourceExperimental — accuracy not yet measured

In the paper

“Delgocitinib (JTE-052/LEO 242549) is a first-generation, non-selective JAK inhibitor that, upon topical and oral application, was shown to improve allergic contact sensitization and AD-like inflammation in animal models221–223.”

What the sources say

• ?Not checked — no full text of the sourcecites [221] Amano, W. et al. The Janus kinase inhibitor JTE-052 improves skin barrier function through suppressing signal transducer and activator of transcription 3 signaling. J. Allergy Clin. Immunol. 136, 667–677 (2015). source
• Partly supported

  The Results section reports that JTE-052 inhibits all four JAK subtypes, supporting its description as a non-selective JAK inhibitor. The paper reports oral effects in mouse cytokine and rat arthritis models, but does not report topical treatment or improvement of allergic contact sensitization or AD-like inflammation; it also does not classify JTE-052 as first-generation. (LLM, conf=0.88)

  cites [222] Tanimoto, A. et al. Pharmacological properties of JTE-052: a novel potent JAK inhibitor that suppresses various inflammatory responses in vitro and in vivo. Inflamm. Res. 64, 41–51 (2015). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [223] Yamamoto, Y. et al. Janus kinase inhibitor delgocitinib suppresses pruritus and nerve elongation in an atopic dermatitis murine model. J. Dermatol. Sci. 97, 161–164 (2020). source

In the paper

“In a phase Ib study with cerdulatinib gel in mild to moderate AD, the compound significantly reduced epidermal thickness, decreased inflammatory DCs and strongly impacted on the inflammatory signature in the transcriptomic analysis232.”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [232] Piscitelli, S. C. et al. A Phase 1b, randomized, single-center trial of topical cerdulatinib (DMVT-502) in patients with mild-to-moderate atopic dermatitis. J. Invest. Dermatol. 141, 1847–1851 (2021). source

In the paper

“The P2X purinoreceptors 3 (P2XR3) are cation channels expressed in sensory neurons that are activated by extracellular ATP and exert an important role in peripheral irritation, pain sensation, coughing but potentially also in itch207–209.”

What the sources say

• ?Not checked — no full text of the sourcecites [207] Dicpinigaitis, P. V., McGarvey, L. P. & Canning, B. J. P2X3-receptor antagonists as potential antitussives: summary of current clinical trials in chronic cough. Lung 198, 609–616 (2020). source
• ?Not checked — no full text of the sourcecites [208] Inoue, K. & Tsuda, M. Nociceptive signaling mediated by P2X3, P2X4 and P2X7 receptors. Biochem. Pharmacol. 187, 114309 (2020). source
• Partly supported

  The Introduction and Abstract describe ATP activation of P2X3-containing receptors on sensory neurons and their role in peripheral irritation and pain. The sensitizing-property section calls them cation channels, and the clinical section reports reduced cough frequency with a P2X3 antagonist. Our copy does not link P2X3 receptors to itch; the only itch mention found is in a reference title. Page numbers are not supplied. (LLM, conf=0.88)

  cites [209] Ford, A. P. & Undem, B. J. The therapeutic promise of ATP antagonism at P2X3 receptors in respiratory and urological disorders. Front. Cell Neurosci. 7, 267v (2013). sourceExperimental — accuracy not yet measured

In the paper

“Atopic dermatitis (AD) is the most common chronic inflammatory skin disease1,2.”

What the sources say

• ?Not checked — no full text of the sourcecites [1] Weidinger, S. & Novak, N. Atopic dermatitis. Lancet 387, 1109–1122 (2016). source
• ?Not checked — no full text of the sourcecites [2] Bieber, T. Atopic dermatitis. N. Engl. J. Med. 358, 1483–1494 (2008). source

In the paper

“The heterogeneous clinical phenotype varies by age, severity and ethnic background5.”

What the sources say

• ?Not checked — no full text of the sourcecites [5] Yew, Y. W., Thyssen, J. P. & Silverberg, J. I. A systematic review and meta-analysis of the regional and age-related differences in atopic dermatitis clinical characteristics. J. Am. Acad. Dermatol. 80, 390–401 (2019). State of the art review on the heterogeneity of the phenotype depending on the ethnic and regional background. source

In the paper

“AD belongs to the spectrum of the atopic disorders, including food allergy, allergic asthma and allergic rhino-conjunctivitis, which are relevant comorbidities10.”

What the sources say

• ?Not checked — no full text of the sourcecites [10] Silverberg, J. I. Comorbidities and the impact of atopic dermatitis. Ann. Allergy Asthma Immunol. 123, 144–151 (2019). source

In the paper

“Moreover, the complexity of the immune pathways that operate in AD offers the opportunity to explore the potential of bispecific or trispecific antibodies.”

In the paper

“Thus, besides efficacy, the long-term safety profile is a key aspect of any new compound in a clinical development programme.”

In the paper

“A dynamic immune response is the hallmark in AD,”

In the paper

“In a phase I/IIa study in 30 patients (10 adults and 20 children), 60% of the adult patients showed 50% reduction in the Scoring of Atopic Dermatitis (SCORAD), while 90% of the paediatric patients achieved Eczema Area Severity Index (EASI) 50 and 30% achieved EASI90 (see the press release from Forte Bioscience in Related links).”

What the sources say

• ?Not matched

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

  cites Forte Bioscience press release

In the paper

“In a phase II trial, a 2% cream formulation showed significant histological and transcriptional modifications, suggesting a dual impact on the barrier function and the inflammatory reaction44.”

What the sources say

• ?Not checked — no full text of the sourcecites [44] Guttman-Yassky, E. et al. ATx201 modulates biomarkers of skin barrier function and cutaneous inflammation in patients with moderate atopic dermatitis. J. Invest. Dermatol. 140, S77 (2020). source

In the paper

“Depending on the individual patient’s natural and unpredictable course of the disorder, its management has two main goals: the rapid and efficacious treatment of acute flares and the far more challenging control of the disease in the long term.”

In the paper

“One of the clinical hallmarks of AD is dry, sensitive and highly permeable skin. This phenotypic characteristic is due to disturbance of epidermal barrier function (Box 1) owing to a dual mechanism1,2,18: first, a genetic origin with mutations in genes encoding functionally important structures such as filaggrin (FLG); and second, an inflammatory origin with key mediators such as IL-13 negatively”

What the sources say

• ?Not checked — no full text of the sourcecites [1] Weidinger, S. & Novak, N. Atopic dermatitis. Lancet 387, 1109–1122 (2016). source
• ?Not checked — no full text of the sourcecites [2] Bieber, T. Atopic dermatitis. N. Engl. J. Med. 358, 1483–1494 (2008). source
• ?Not checked — no full text of the sourcecites [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. source

In the paper

“Following the same strategy of bacteriotherapy, topical application of a lyophilized strain of Staphylococcus hominis A9 (ShA9) with the dual activity of killing Staphylococcus aureus and inhibiting the production of S. aureus-derived toxins, allowed the microbiome to recover.”

What the sources say

• ?Not checked — no full text of the sourcecites [43] Nakatsuji, T. et al. Development of a human skin commensal microbe for bacteriotherapy of atopic dermatitis and use in a phase 1 randomized clinical trial. Nat. Med. 27, 700–709 (2021). source

In the paper

“A product combining three strains of R. mucosa (FB-401) has been developed and explored, with its therapeutic activity likely consisting of activation of tissue repair and anti-inflammatory activity via Toll-like receptor 5 (TLR5) and tumour necrosis factor receptor (TNFR)42.”

What the sources say

• ?Not checked — no full text of the sourcecites [42] Myles, I. A. et al. Therapeutic responses to Roseomonas mucosa in atopic dermatitis may involve lipid-mediated TNF-related epithelial repair. Sci. Transl Med. 12, eaaz8631 (2020). source

In the paper

“The epidermal barrier function is subjected to dual regulation57,252: first, an intrinsic genetic mechanism whereby genes encoding structural elements such as filaggrin (FLG) are subjected to mutations or variants252 and, second, an underlying inflammation that modulates the expression of epidermal structural components253–256 and thereby further aggravates the barrier dysfunction.”

What the sources say

• ?Not checked — no full text of the sourcecites [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. source
• ?Not checked — no full text of the sourcecites [252] Irvine, A. D., McLean, W. H. & Leung, D. Y. Filaggrin mutations associated with skin and allergic diseases. N. Engl. J. Med. 365, 1315–1327 (2011). source
• ?Not checked — no full text of the sourcecites [253] Howell, M. D. et al. Cytokine modulation of atopic dermatitis filaggrin skin expression. J. Allergy Clin. Immunol. 120, 150–155 (2007). Shows how the inflammatory reaction impacts on the function of the epidermal barrier in AD. source
• ?Not checked — no full text of the sourcecites [254] Kim, B. E., Leung, D. Y., Boguniewicz, M. & Howell, M. D. Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6. Clin. Immunol. 126, 332–337 (2008). source
• ?Not checked — no full text of the sourcecites [255] Howell, M. D. et al. Th2 cytokines act on S100/A11 to downregulate keratinocyte differentiation. J. Invest. Dermatol. 128, 2248–2258 (2008). source
• ?Not checked — no full text of the sourcecites [256] Berdyshev, E. et al. Lipid abnormalities in atopic skin are driven by type 2 cytokines. JCI Insight 3, e98006 (2018). source

In the paper

“While well tolerated, ShA9 also induced a modest improvement of skin lesions as measured by EASI and SCORAD43.”

What the sources say

• ?Not checked — no full text of the sourcecites [43] Nakatsuji, T. et al. Development of a human skin commensal microbe for bacteriotherapy of atopic dermatitis and use in a phase 1 randomized clinical trial. Nat. Med. 27, 700–709 (2021). source

In the paper

“Antigen presentation has a crucial role in the generation and maintenance of the various pathways of the adaptive immune response, ultimately leading to inflammation.”

In the paper

“dupilumab is now approved for children aged 6 years and older”

In the paper

“In a phase IIb trial, the best results were obtained with a 1% cream61,62, with 53% of the patients reaching the primary end point of Investigator Global Assessment (IGA) 0/1 versus 28% in the placebo group.”

What the sources say

• ?Not checked — no full text of the sourcecites [61] Paller, A. S. et al. Efficacy and patient-reported outcomes from a phase 2b, randomized clinical trial of tapinarof cream for the treatment of adolescents and adults with atopic dermatitis. J. Am. Acad. Dermatol. 84, 632–638 (2020). source
• ?Not checked — no full text of the sourcecites [62] Peppers, J. et al. A phase 2, randomized dose-finding study of tapinarof (GSK2894512 cream) for the treatment of atopic dermatitis. J. Am. Acad. Dermatol. 80, 89–98 (2019). First report on the improvement of AD upon topical AhR antagonist treatment. source

In the paper

“An interim data analysis from a phase Ib study showed that the compound is well tolerated and provided promising efficacy data, with 67% of the patients achieving EASI75 versus 0% in the placebo group”

What the sources say

• ?Not matched

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

  cites ASLAN press release

In the paper

“Interestingly, coal tar has been shown to bind to AhR and to restore the expression of filaggrin, as shown by immunohistochemistry and transcriptomic analysis59.”

What the sources say

• ?Not checked — no full text of the sourcecites [59] van den Bogaard, E. H. et al. Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis. J. Clin. Invest. 123, 917–927 (2013). source

In the paper

“In an open-label phase IIa study in eight patients, the safety profile of bermekimab was acceptable, and results for the highest dose indicated promising efficacy, with 39% of patients reaching the status of clear or almost clear (IGA 0/1) as well as a strong reduction in itching, with 68% improvement in the pruritus numerical rating scale (NRS) (see results under NCT03496974).”

What the sources say

• ?Not matched

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

  cites NCT03496974

In the paper

“OX40 is a costimulatory molecule and member of the TNF receptor family (TNFRS4).”

In the paper

“It is transiently expressed on T cells upon activation and contributes to clonal expansion, survival and memory formation.”

In the paper

“Similarly, in a phase Ib trial, KHK4083 resulted in a 74% reduction in the EASI score, and the IGA 0/1 was reached in 35% of the patients79.”

What the sources say

• ?Not checked — no full text of the sourcecites [79] Nakagawa, H. et al. Safety, tolerability and efficacy of repeated intravenous infusions of KHK4083, a fully human anti-OX40 monoclonal antibody, in Japanese patients with moderate to severe atopic dermatitis. J. Dermatol. Sci. 99, 82–89 (2020). source

In the paper

“In a phase IIa trial, intravenous GBR 830 was well tolerated and significantly improved the lesions with an EASI50 in 78% of patients who received the antibody, compared with 38% in the placebo group.”

What the sources say

• ?Not checked — no full text of the sourcecites [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. source

In the paper

“The limitations of this study were small sample size (n = 60) and a time point likely too early to capture the clinical effects.”

In the paper

“Lebrikizumab does not affect the binding of IL-13 to the IL-13Rα2 receptor chain, the biological role of which remains unclear81.”

What the sources say

• ?Not checked — no full text of the sourcecites [81] Gandhi, N. A. et al. Targeting key proximal drivers of type 2 inflammation in disease. Nat. Rev. Drug Discov. 15, 35–50 (2016). Key review paper on the targeted therapy aiming to alter the dominant TH2 pathways in allergic disorders. source

In the paper

“Tralokinumab, which was recently backed by a positive opinion from the EMA (EMA/CHMP/202204/2021), is a fully humanized antibody targeting IL-13 that blocks its binding to both IL-13Rα1 and IL-13α2 receptor chains90,91.”

What the sources say

• ?Not checked — no full text of the sourcecites [90] Popovic, B. et al. Structural characterisation reveals mechanism of IL-13-neutralising monoclonal antibody tralokinumab as inhibition of binding to IL-13ralpha1 and IL-13Ralpha2. J. Mol. Biol. 429, 208–219 (2017). source
• ?Not checked — no full text of the sourcecites [91] May, R. D. & Fung, M. Strategies targeting the IL-4/IL-13 axes in disease. Cytokine 75, 89–116 (2015). source

In the paper

“These encouraging efficacy data were confirmed by reduced use of TCSs as well as improved quality of life in the omalizumab-treated group.”

In the paper

“in a first proof-of-concept study of the anti-IL-5 antibody mepolizumab, although eosinophilia was significantly reduced99, the drug failed to demonstrate a significant decrease in the SCORAD, the pruritus scoring or the severity biomarker TARC when compared with baseline.”

What the sources say

• ?Not checked — no full text of the sourcecites [99] Oldhoff, J. M. et al. Anti-IL-5 recombinant humanized monoclonal antibody (mepolizumab) for the treatment of atopic dermatitis. Allergy 60, 693–696 (2005). source

In the paper

“Eosinophils and their degradation products eosinophil-derived neurotoxin and eosinophil cationic protein are detectable in the inflammatory infiltrate of AD and correlate with disease severity97,98.”

What the sources say

• ?Not checked — no full text of the sourcecites [97] Byeon, J. H. et al. Correlation of serum interleukin-31 with pruritus and blood eosinophil markers in children with atopic dermatitis. Allergy Asthma Proc. 41, 59–65 (2020). source
• ?Not checked — no full text of the sourcecites [98] Kim, H. S. et al. Eosinophil-derived neurotoxin as a biomarker for disease severity and relapse in recalcitrant atopic dermatitis. Ann. Allergy Asthma Immunol. 119, 441–445 (2017). source

In the paper

“Dupilumab is also approved for atopic comorbidities such as allergic asthma and nasal polyposis”

In the paper

“The rate of conjunctivitis was low and the drug was otherwise well tolerated.”

In the paper

“Although increased IgE serum level is a hallmark of a TH2 immune response and specific IgE to at least one allergen can be found in the vast majority of AD patients”

In the paper

“In the phase III pivotal monotherapy studies, at week 16, tralokinumab showed superiority to placebo, with IGA 0/1 being reached in 16% (ECZTRA1) and 22% (ECZTRA2) of the patients receiving the antibody versus 7% and 11% in the respective placebo groups.”

In the paper

“Anti-CεmX (FB825) is directed against mIgE and has been reported to deplete IgE-committed B cells and lymphoblasts by apoptosis.”

What the sources say

• ?Not checked — no full text of the sourcecites [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. source

In the paper

“The drug is already approved for severe forms of eosinophilic asthma and a phase IIa study in AD exploring its efficacy in a maintenance regimen (HILLIER study) is ongoing.”

In the paper

“benralizumab binds to the IL-5Rα chain expressed on eosinophils and basophils and initiates antibody-dependent cell-mediated cytotoxicity, ultimately leading to their depletion.”

In the paper

“In the early 1980s, increased PDE4 activity was described as one of the first candidate targets for the therapy of allergic disorders including AD126,127.”

What the sources say

• ?Not checked — no full text of the sourcecites [126] Ungar, B. et al. Phase 2 randomized, double-blind study of IL-17 targeting with secukinumab in atopic dermatitis. J. Allergy Clin. Immunol. 147, 394–397 (2021). source
• ?Not checked — no full text of the sourcecites [127] Grewe, S. R., Chan, S. C. & Hanifin, J. M. Elevated leukocyte cyclic AMP-phosphodiesterase in atopic disease: a possible mechanism for cyclic AMP-agonist hyporesponsiveness. J. Allergy Clin. Immunol. 70, 452–457 (1982). source

In the paper

“Although the highest dose showed an interesting effect on the pruritus score, the absolute change in EASI from baseline was not significant when compared with placebo and thereby not superior to pimecrolimus (NCT01037881).”

What the sources say

• ?Not matched

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

  cites NCT01037881

In the paper

“While H4R antagonism alone seems promising in reducing the scratching reaction in animal models of skin inflammation, it only improves inflammation in combination with H1R antagonism147.”

What the sources say

• ?Not checked — no full text of the sourcecites [147] Kochling, H. et al. Combined treatment with H1 and H4 receptor antagonists reduces inflammation in a mouse model of atopic dermatitis. J. Dermatol. Sci. 87, 130–137 (2017). source

In the paper

“this compound did not show clinical efficacy or induce any significant changes in several mechanistic investigations such as epidermal thickness, changes in the composition of the cellular infiltrate or analysis of the transcriptomic signatures126.”

What the sources say

• ?Not checked — no full text of the sourcecites [126] Ungar, B. et al. Phase 2 randomized, double-blind study of IL-17 targeting with secukinumab in atopic dermatitis. J. Allergy Clin. Immunol. 147, 394–397 (2021). source

In the paper

“administration of the PDE4 inhibitor roflumilast (AQR-151) as a cream failed to reach the primary end point (change in EASI from baseline) and there were no safety signals.”

In the paper

“H3R is localized in the central nervous system, where it regulates the synthesis of histamine.”

In the paper

“Four types of histamine receptor (H1R–H4R) have been described, all of which are G protein-coupled receptors137.”

What the sources say

• ?Not checked — no full text of the sourcecites [137] Cataldi, M., Borriello, F., Granata, F., Annunziato, L. & Marone, G. Histamine receptors and antihistamines: from discovery to clinical applications. Chem. Immunol. Allergy 100, 214–226 (2014). source

In the paper

“H4R exerts immunoregulatory activities on leukocytes and represents an interesting target for immunomodulation.”

In the paper

“A phase IIb dose-ranging study with adriforant was terminated and the programme was suspended.”

In the paper

“a modest but significant improvement in the SCORAD was shown, but the reduction in pruritus was not significant148.”

What the sources say

• ?Not checked — no full text of the sourcecites [148] Werfel, T., Asher, A., Tsianakas, A., Gupta, B. & Sarmiento, R. A phase 2a proof of concept clinical trial to evaluate ZPL-3893787 (ZPL-389), a potent, oral histamine H-4 receptor antagonist for the treatment of moderate to severe atopic dermatitis (AD) in adults. Allergy 71, 95–95 (2016). source

In the paper

“H2R is mainly localized in the gastrointestinal tract and other organs, where it regulates smooth muscle relaxation.”

In the paper

“H1R in the brain is involved in internal clock modulation, while in the skin, it induces pruritus but also has immunomodulatory activities.”

In the paper

“A strategy aimed at enforcing the Treg cell limb of the immune system would restore tolerance and repress chronic inflammation.”

In the paper

“The pegylated recombinant human IL-2 (rhIL-2; LY3471851) has been designed to target the IL-2 receptor complex on T cells leading to activation and proliferation of Treg cells.”

In the paper

“the oral PDE4 inhibitor apremilast is already approved to treat moderate to severe forms of psoriasis while its development in AD fails to progress.”

In the paper

“the C-C chemokine receptor 4 (CCR4/CD194) is a hallmark of memory TH2 cells and binds to the chemokines RANTES, MCP1, CCL22/MDC and CCL17/TARC.”

In the paper

“The multiple biological activities of S1P are mediated by five distinct G protein-coupled receptors (S1PR1–5), which are differently expressed in various tissues163.”

What the sources say

• ?Not checked — no full text of the sourcecites [163] Rivera, J., Proia, R. L. & Olivera, A. The alliance of sphingosine-1-phosphate and its receptors in immunity. Nat. Rev. Immunol. 8, 753–763 (2008). source

In the paper

“Of note, the study included a high proportion of patients with a moderate form of AD.”

In the paper

“As soon as at week 4, significant changes in peak pruritus NRS (PP-NRS) and the secondary end point EASI75 were observed”

What the sources say

• ?Not matched

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

  cites press statement

In the paper

“Although they act initially as S1PR agonists, they promote receptor internalization and so are functional antagonists in the longer term.”

In the paper

“Although the phase I trial generated promising results for psoriasis, no reports are currently available with regard to its use in AD.”