A preprint by Zhu et al. shows that protease allergens induce neural hypersensitivity by activating mTORC1 signalling in sensory neurons.

Cutaneous allergen sensitization (CAS) underlies atopic dermatitis (AD) and leads to various allergic symptoms, including food allergy and anaphylaxis. IL-13 expression by T follicular helper T (TFH) has been reported to be involved in generating high-affinity IgE antibodies and causing systemic anaphylaxis.1, 2 However, the mechanisms by which IL-13 triggers IgE-mediated allergic responses remain poorly defined. In the present study, we elucidate the role of IL-13 in the CAS-mediated mechanism by which high-affinity IgE antibodies are produced when the same allergen is introduced at a distal site in the secondary sensitization. The CAS model system using mice lacking the cell lineage-specific IL-13 receptor (IL-13R) demonstrated that dendritic cells (DCs), but not T or B cells, are critical in the high-affinity IgE-mediated anaphylactic response. The IL-13 signal in type 2 conventional DCs (cDC2s) enhanced the expression of MHC class II and CD301b, which was essential for the recall of type 2 responses, inducing the production of high-affinity IgE antibodies. Similar IL-13R-expressing DCs were identified in allergic rhinitis and food allergy patients with a history of AD. These findings strongly suggest the importance of DC-specific IL-13 signaling in CAS-induced allergic reactions associated with the atopic march, which is common in human AD patients.

Background Amlitelimab is an anti-OX40 Ligand (OX40L) monoclonal antibody inhibiting OX40L-OX40 interactions. Here, we evaluated itch response in clinical responders at Week 24 who continued or withdrew from amlitelimab treatment for an additional 28 weeks in Part 2 of the Phase 2b STREAM-AD (NCT05131477) dose-ranging trial in adults with moderate-to-severe AD. Methods STREAM-AD Part 2 included 190 clinical responders from Part 1, defined as those achieving EASI-75 and/or IGA 0/1 at Week 24. Participants were re-randomized 3:1 to withdraw treatment or continue pre-Week 24 dose (250mg with 500mg loading dose, n=34 [treatment withdrawal]/n=13 [continuing]; 250mg, n=28/n=12; 125mg, n=33/n=12; 62.5mg, n=35/n=7; placebo responders continuing placebo, n=16), and were followed to Week 52 for efficacy. In this post hoc analysis, proportions of patients with a ≥4-point reduction from baseline in Peak Pruritus Numerical Rating Scale (PPNRS≥4) were evaluated in clinical responders at Weeks 24 and 52. Results Of the participants entering Part 2 who received amlitelimab in Part 1 (n=174), 46.6% (n=81) were PPNRS≥4 responders. Among these Week 24 PPNRS≥4 responders that continued (n=27) or withdrew (n=54) from amlitelimab during Part 2, 74.1% and 63.0% maintained PPNRS≥4 responses at Week 52, respectively. Conclusion In the STREAM-AD Phase 2b trial, many patients treated with amlitelimab who demonstrated skin improvements also experienced improvements in itch at Week 24. A majority of the clinical responders who saw itch reduction at Week 24 maintained this reduction on- or off-amlitelimab for the 28-week withdrawal period, demonstrating durable and sustained itch responses following amlitelimab treatment.

Visceral pain disorders such as interstitial cystitis/bladder pain syndrome (IC/BPS) and irritable bowel syndrome (IBS) often manifest concurrently in the bladder and colon. Yet, the mechanistic basis of such comorbidities and the transmission of neural hypersensitivity across organ systems has remained a mystery. Here, we identify a mast cell-sensory neuron circuit that initiates bladder inflammation and simultaneously propagates neural hypersensitivity to the colon in a murine model of IC/BPS. We unveil anatomic heterogeneity of mast cells in relation to nociceptors in the bladder and their critical dependence on Mas-related G protein-coupled receptor B2 (MrgprB2) to promote visceral hypersensitivity. Employing retrograde neuronal tracing, in vivo calcium imaging, and intersectional genetics, we uncover a population of polyorganic sensory neurons that simultaneously innervate multiple organs and exhibit functional convergence. Importantly, using humanized mice, we demonstrate that pharmacological blockade of mast cell-expressed MRGPRX2, the human ortholog of MrgprB2, attenuates both bladder pathology and colonic hypersensitivity. Our studies reveal evolutionarily conserved neuroimmune mechanisms by which immune cells can directly convey signals from one organ to another through sensory neurons, in the absence of physical proximity, representing a new therapeutic paradigm.

Objective The heterogeneous nature of atopic dermatitis (AD) necessitates flexibility in tailoring treatment regimens to manage changes in the signs and symptoms of AD over time. Abrocitinib, an oral Janus kinase 1–selective inhibitor, is approved for the treatment of adults and adolescents with moderate-to-severe AD. The objective of this study was to assess durability of response after treatment interruption in patients with moderate-to-severe AD receiving abrocitinib. Methods This analysis included patients from JADE REGIMEN (NCT03627767) who received abrocitinib 200 mg for 12 weeks, were responders (Investigator’s Global Assessment [IGA] score of 0/1 with ≥2-point reduction from baseline and ≥75% improvement from baseline in Eczema Area and Severity Index [EASI-75]), and then received placebo for 40 weeks. In case of flare (≥50% loss of initial EASI response at Week 12 with a new IGA score ≥2), patients restarted abrocitinib as rescue therapy (abrocitinib 200 mg plus topical therapy) for 12 weeks. Patients then entered an ongoing long-term extension study (JADE EXTEND [NCT03422822]; data cutoff: September 5, 2022) and were randomly assigned to abrocitinib 200 mg or 100 mg. Assessments included EASI-75 and ≥90% improvement from baseline in EASI (EASI-90). Missing data were handled with nonresponder imputation (NRI). Results Of 234 responders who were randomized to placebo and entered EXTEND, 42 (18%) did not have flares on placebo for 40 weeks: of these, 16 and 26 then received abrocitinib 200 mg and 100 mg in EXTEND, respectively. Of patients who had flares and received rescue therapy, 49 and 143 received abrocitinib 200 mg and 100 mg in EXTEND. Of flare-free patients, 93.8%/68.0% (200 mg/100 mg) and 81.3%/48.0% achieved EASI-75 and EASI-90, respectively, at last assessment on placebo; 87.5%/60.0% and 75.0%/56.0% maintained response (NRI) at 48 weeks after restarting abrocitinib. Of patients who had flares, 97.8%/94.3% (200 mg/100 mg) and 73.9%/82.9% achieved EASI-75 and EASI-90, respectively, at Week 12 of rescue therapy; 76.6%/59.3% and 72.3%/41.4% maintained response (NRI) at 96 weeks after initiating rescue therapy. Conclusion For some patients receiving abrocitinib treatment, treatment may be interrupted without these patients experiencing a loss of response. In case of flare, restarting abrocitinib is an effective, fast rescue therapy. Restarting abrocitinib treatment showed good response at either dose, although response rates were numerically higher with abrocitinib 200 mg.

There is a need for rapid management of the debilitating symptoms of prurigo nodularis (PN), particularly the characteristically severe pruritus. Nemolizumab blocks interleukin (IL)-31, the first neuroimmune cytokine described to directly trigger pruritus. IL-31 also has an important role in inflammatory pathways, epidermal dysregulation and fibrotic responses. We analysed data from the pivotal phase III randomized controlled trials, OLYMPIA 1 and 2, to characterize the onset of action on additional pruritus metrics and sleep disturbances in patients with moderate-to-severe PN. In OLYMPIA 1 and 2 combined, 560 adult patients were randomized to receive an initial 60-mg dose of nemolizumab subcutaneously followed by nemolizumab 30 mg or 60 mg (depending on weight) (n = 373) or matching placebo (n = 187) every 4 weeks for 16 weeks (OLYMPIA 2) or 24 weeks (OLYMPIA 1). We analysed the daily response rates on itch-free or nearly itch-free status and a clinically meaningful improvement (≥ 4-point improvement from baseline) on daily Peak Pruritus Numerical Rating Scale (PP-NRS) and Sleep Disturbance Numerical Rating Scale (SD-NRS). Nearly itch free was defined as a mean daily PP-NRS < 2. By day 4, the proportion of itch-free or nearly itch-free patients was significantly greater with nemolizumab (5.5–6.8%) than with placebo (0–1.3%) in OLYMPIA 1 and 2 (P < 0.05). Further, in a pooled analysis of OLYMPIA 1 and 2, the proportion of patients with ≥ 4-point improvement from baseline in daily PP-NRS differed significantly between groups as early as day 1 (11.0% nemolizumab vs. 2.1% placebo, P = 0.001), similarly to previous results (Ständer S, Elmariah S, Kwatra SG et al. Nemolizumab elicits an early and rapid itch response in prurigo nodularis within 2 days: a post hoc analysis of OLYMPIA 1&2 data. Presented at the European Academy of Dermatology and Venereology Annual Meeting, Amsterdam, the Netherlands, 25–28 September 2024). Improvements in sleep also occurred rapidly. The proportion of patients with ≥ 4-point improvement from baseline in daily SD-NRS was significantly higher for nemolizumab compared with placebo by day 1 (pooled data: 8.8% vs. 3.7%, P = 0.03). As with pruritus, the differences between groups increased over time. With pruritus being the most burdensome symptom of PN, early control of itch provides an important benefit for patients. As consistently shown in both studies, rapid reduction in itch with nemolizumab translates to improved sleep. This work was sponsored by Galderma SA and Galderma UK.

Mast cell activation syndrome (MCAS) is a term applied to several clinical entities which have gained increased attention from patients and medical providers. While several descriptive publications about MCAS exist, there are many gaps in knowledge resulting in confusion about this clinical syndrome. Whether MCAS is a primary syndrome or exists as a constellation of symptoms in the context of known inflammatory, allergic, or clonal disorders associated with systemic mast cell (MC) activation is not well understood. More importantly, the underlying mechanisms and pathways that lead to MC activation in MCAS patients remain to be elucidated.The purpose of this manuscript is to summarize the known literature, identify gaps in knowledge, and highlight research needs. Several topics are covered: 1) Contextualization of MCAS and MCAS-like endotypes and related diagnostic evaluations; 2) Mechanistic research; 3) Management of typical and refractory symptoms, and 4) MCAS-specific education for patients and healthcare providers.

Background: Previous reports show that dupilumab treatment reduces IgE levels in patients with moderate-to-severe atopic dermatitis (AD). This analysis reports the impact of dupilumab-induced reduction in total IgE levels on flare probability in patients with moderate-to-severe AD.

IgE levels are often elevated in patients with atopic dermatitis (AD) but the clinical relevance of reducing IgE levels in patients with AD remains unclear. This analysis reports the impact of dupilumab treatment on total IgE levels in association with the probability of having flares in patients with moderate-to-severe AD.

Importance Chronic pruritus, defined as itch experienced for 6 weeks or longer, affects approximately 22% of people in their lifetime. Approximately 1% of physician visits are for the chief concern of chronic pruritus. Chronic pruritus is associated with adverse outcomes, including impaired sleep and reduced quality of life. Observations Chronic pruritus can be categorized by etiology into inflammatory, neuropathic, or a combination of inflammatory and neuropathic pruritus. Chronic pruritus is due to inflammation in approximately 60% of patients and may be caused by eczema, psoriasis, or seborrheic dermatitis. Chronic pruritus is due to a neuropathic or mixed etiology in approximately 25% of patients. Neuropathic causes of chronic pruritus include postherpetic neuralgia and notalgia paresthetica and are typically due to localized or generalized nerve dysregulation. Approximately 15% of people with chronic pruritus have other causes including systemic diseases with secondary itch, such as uremic pruritus and cholestatic pruritus, medication-induced pruritus such as pruritus due to immunotherapy, and infectious etiologies such as tinea corporis and scabies. When few primary changes are present, a thorough history, review of symptoms, and laboratory evaluation should be performed, particularly for people with chronic pruritus lasting less than 1 year. Clinicians should consider the following tests: complete blood cell count, complete metabolic panel, and thyroid function testing to evaluate for hematologic malignancy, liver disease, kidney disease, or thyroid disease. First-line treatment for inflammatory chronic pruritus includes topical anti-inflammatory therapies such as hydrocortisone (2.5%), triamcinolone (0.1%), or tacrolimus ointment. Approximately 10% of patients do not respond to topical therapies. In these patients, referral to dermatology and systemic oral or injectable treatments such as dupilumab or methotrexate may be considered. When no underlying systemic disease associated with pruritus is identified, patients are likely to have neuropathic chronic pruritus or mixed etiology such as chronic pruritus of unknown origin. In these patients, neuropathic topical treatments such as menthol, pramoxine, or lidocaine can be used either alone or in combination with immunomodulatory agents such as topical steroids. Other effective therapies for neuropathic pruritus include gabapentin, antidepressants such as sertraline or doxepin, or opioid receptor agonist/antagonists such as naltrexone or butorphanol. Conclusions and Relevance Chronic pruritus can adversely affect quality of life and can be categorized into inflammatory, neuropathic, or a combined etiology. First-line therapies are topical steroids for inflammatory causes, such as hydrocortisone (2.5%) or triamcinolone (0.1%); topical neuropathic agents for neuropathic causes, such as menthol or pramoxine; and combinations of these therapies for mixed etiologies of chronic pruritus.

ImportancePrurigo nodularis (PN) is a debilitating skin disease characterized by the hallmark symptom of chronic itch; the intensity of itch in PN was assessed using the Worst Itch Numeric Rating Scale (WI-NRS) to evaluate the primary efficacy end point of 2 recent phase 3 studies of dupilumab treatment for PN.ObjectiveTo validate the psychometric properties and to determine the clinically meaningful improvement threshold for WI-NRS in patients with moderate to severe PN.Design, Setting, and ParticipantsIn this secondary analysis of the PRIME and PRIME2 trials, content validity of WI-NRS was assessed through in-depth patient interviews. Psychometric assessments used pooled data from masked, intention-to-treat (ITT) patients with PN from randomized, double-masked, and placebo-controlled studies. Psychometric assessments included test-retest reliability, construct validity, known-groups validity, and sensitivity to change in adult patients with moderate-to-severe PN. Thresholds for meaningful within-patient improvement in the WI-NRS score were determined using anchor and distribution-based approaches. Data were analyzed after completion of each study, December 2019 to November 2021 for PRIME and January 2020 to August 2021 for PRIME2.ExposuresDupilumab (300 mg) or placebo subcutaneously every 2 weeks for 24 weeks.Main outcomes and measuresWI-NRS score at specified time points up to 24 weeks after randomization.ResultsA total of 20 patients were included across the 2 studies (mean [SD] age, 49.3 [17.2] years; 11 female [55%]); 311 patients were included in the pooled intention-to-treat analysis (mean [SD] age, 49.5 [16.1] years; 203 female [65.3%]). The WI-NRS questions (20 of 20 patients), recall period (19 of 20 patients), and response scale (20 of 20 patients) were easy to understand and relevant for patients with PN. Adequate test-retest reliability was observed between screening and baseline (intraclass correlation coefficient = 0.72, using Patient Global Impression of Severity [PGIS] to define stable patients). Convergent and discriminant validity was supported by moderate to strong correlations (absolute r range = 0.34-0.73) with other conceptually related measures and weaker correlations (absolute r range = 0.06-0.32) with less-related measures, respectively. WI-NRS was sensitive to change, as demonstrated by differences in change from baseline among groups (per PGIS change and PGI of Change [PGIC]). Using anchor-based approach with PGIS and PGIC, the clinically meaningful improvement threshold was 4 points (range, 3.0-4.5), which was also supported by distribution-based methods.Conclusion and RelevanceThis study found that WI-NRS may be a fit-for-purpose instrument to support efficacy end points measuring the intensity of itching in adults with PN.Trial RegistrationNCT04183335 (PRIME) and NCT04202679 (PRIME2)

PurposeBased on a potential shared pathophysiology tied to mast cell activity and neurogenic inflammation that may link pruritus and chronic cough (CC), this study, leveraging the All of Us database, examines the association between the two conditions.Materials and methodsA nested case-control comparison was used to examine the association, identifying cases with SNOMED codes 418363000 (pruritus) and 68154008 (CC). Matching was performed on a 1:4 ratio by age, sex, and ethnicity using the MatchIt package in R, followed by maximum likelihood method to estimate odds ratios (ORs) and 95% confidence intervals from 2x2 contingency tables.ResultsCC patients (n = 2,388) were more than twice as likely to be diagnosed with pruritus (OR: 2.65) and pruritus patients (n = 22,496) were more than twice as likely to be diagnosed with CC (OR: 2.57), than respective matched controls.ConclusionsThese results highlight the potential bidirectional relationship between CC and pruritus, suggesting possible shared immune and neural pathways. Treatments like difelikefalin and nalbuphine that modulate these pathways, alongside P2X3 targeting agents, are emerging as potential therapeutic approaches for itch and chronic cough given the possible interconnected pathophysiology. This study's insights into the associations between pruritus and CC may pave the way for targeted therapeutic strategies that address their shared mechanisms.

Introduction: Atopic dermatitis (AD), prurigo nodularis (PN), and chronic spontaneous urticaria (CSU) are chronic inflammatory skin diseases varying in clinical presentation but sharing the common and burdensome symptom of itch.

Atopic dermatitis (AD), with its hallmark symptoms of pruritus and skin lesions, often impairs patients’ quality of life. We assessed time spent with clear/almost clear skin and no/minimal itch during upadacitinib treatment versus placebo or dupilumab among patients with moderate-to-severe AD. This analysis consisted of a post hoc analysis of Measure Up 1 (NCT03569293), Measure Up 2 (NCT03607422), and Heads Up (NCT03738397). Measure Up 1 and 2 were replicate, randomized, double-blind, placebo-controlled phase 3 studies with patients randomized (1:1:1) to once-daily oral upadacitinib 15 mg, upadacitinib 30 mg, or placebo for 16 weeks. Heads Up was a head-to-head, randomized, double-blind, double-dummy, phase 3b study with patients randomized (1:1) to upadacitinib 30 mg or subcutaneous dupilumab 300 mg for 24 weeks. Skin clearance was assessed with the Eczema Area and Severity Index (EASI) at baseline, weeks 1, 2, and 4, and every 4 weeks thereafter. Itch was assessed using the Worst Pruritus Numerical Rating Scale (WP-NRS) daily over 16 weeks and every 2 weeks thereafter to week 24 in Heads Up. This analysis included 1683 patients in Measure Up 1 and 2 and 673 patients in Heads Up. Through 16 weeks in Measure Up 1 and 2, patients receiving upadacitinib spent 9.8–13.4 times as many days with an EASI 90 response and 7.0–10.3 times as many days with a WP-NRS 0/1 response versus placebo. In Heads Up, patients receiving upadacitinib spent 2.0 and 1.7 times as many days through 16 and 24 weeks, respectively, with an EASI 90 response versus dupilumab. Through 16 and 24 weeks, patients receiving upadacitinib spent 3.0 and 2.6 times as many days, respectively, with a WP-NRS 0/1 response versus dupilumab. Patients with moderate-to-severe AD spent more time with clear/almost clear skin and no/minimal itch with upadacitinib versus placebo or dupilumab. ClinicalTrials.gov identifier, Measure Up 1 (NCT03569293), Measure Up 2 (NCT03607422), Heads Up (NCT03738397).

Abstract Introduction/Background Atopic dermatitis is a chronic inflammatory skin disease characterized by intense and debilitating pruritus – its most burdensome symptom – and requires long-term control. Results from the Heads Up trial (NCT03738397) found that upadacitinib (UPA) 30 mg was superior to dupilumab (DUPI) 300 mg for improving itch as indicated by increases in the percent of improvement from baseline for Worst Pruritus NRS scores (WP-NRS). Objective This analysis compared the proportion of days patients treated with UPA or DUPI spent in itch response states indicated by WP-NRS. Methods Heads Up was a 24-week head-to-head phase 3b multicenter, randomized, double-blind study comparing UPA 30 mg to DUPI 300 mg in adults with moderate-to-severe AD. We compared the proportion of days patients treated with UPA or DUPI spent in an improved-itch state (WP-NRS improvement ≥4 relative to baseline; among patients with baseline WP-NRS ≥4) or a state of no/minimal itch (WP-NRS 0/1; among patients with baseline WP-NRS >1). Results Participants included 673 patients randomized into two groups: those taking UPA (N=342) or DUPI (N=331). At 4 and 16 weeks, patients treated with UPA vs DUPI spent a greater proportion of days in an improved-itch state (week 4: 50.0% vs 19.3%; week 16: 60.4% vs 35.7%), and in a state of no/minimal itch (week 4: 22.1% vs 4.3%; week 16: 34.4% vs 11.4%). Conclusions Treatment of moderate-to-severe AD with UPA 30 mg daily resulted in a greater proportion of days spent with meaningful itch improvement (WP-NRS improvement ≥4) and more time with no/minimal itch (WP-NRS 0/1) compared to treatment with DUPI over 4 and 16 weeks.

Importance:Chronic pruritus, defined as itch experienced for 6 weeks or longer, affects approximately 22% of people in their lifetime. Approximately 1% of physician visits are for the chief concern of chronic pruritus. Chronic pruritus is associated with adverse outcomes, including impaired sleep and reduced quality of life. Observations:Chronic pruritus can be categorized by etiology into inflammatory, neuropathic, or a combination of inflammatory and neuropathic pruritus. Chronic pruritus is due to inflammation in approximately 60% of patients and may be caused by eczema, psoriasis, or seborrheic dermatitis. Chronic pruritus is due to a neuropathic or mixed etiology in approximately 25% of patients. Neuropathic causes of chronic pruritus include postherpetic neuralgia and notalgia paresthetica and are typically due to localized or generalized nerve dysregulation. Approximately 15% of people with chronic pruritus have other causes including systemic diseases with secondary itch, such as uremic pruritus and cholestatic pruritus, medication-induced pruritus such as pruritus due to immunotherapy, and infectious etiologies such as tinea corporis and scabies. When few primary changes are present, a thorough history, review of symptoms, and laboratory evaluation should be performed, particularly for people with chronic pruritus lasting less than 1 year. Clinicians should consider the following tests: complete blood cell count, complete metabolic panel, and thyroid function testing to evaluate for hematologic malignancy, liver disease, kidney disease, or thyroid disease. First-line treatment for inflammatory chronic pruritus includes topical anti-inflammatory therapies such as hydrocortisone (2.5%), triamcinolone (0.1%), or tacrolimus ointment. Approximately 10% of patients do not respond to topical therapies. In these patients, referral to dermatology and systemic oral or injectable treatments such as dupilumab or methotrexate may be considered. When no underlying systemic disease associated with pruritus is identified, patients are likely to have neuropathic chronic pruritus or mixed etiology such as chronic pruritus of unknown origin. In these patients, neuropathic topical treatments such as menthol, pramoxine, or lidocaine can be used either alone or in combination with immunomodulatory agents such as topical steroids. Other effective therapies for neuropathic pruritus include gabapentin, antidepressants such as sertraline or doxepin, or opioid receptor agonist/antagonists such as naltrexone or butorphanol. Conclusions and Relevance:Chronic pruritus can adversely affect quality of life and can be categorized into inflammatory, neuropathic, or a combined etiology. First-line therapies are topical steroids for inflammatory causes, such as hydrocortisone (2.5%) or triamcinolone (0.1%); topical neuropathic agents for neuropathic causes, such as menthol or pramoxine; and combinations of these therapies for mixed etiologies of chronic pruritus.

Atopic dermatitis (AD) is a chronic, relapsing immunoinflammatory skin condition characterized by sensations such as pruritis, pain, and neuronal hypersensitivity. The mechanisms underlying these sensations are multifactorial and involve complex crosstalk among several cutaneous components. This review explores the role these components play in the pathophysiology of atopic dermatitis. In the skin intercellular spaces, sensory nerves interact with keratinocytes and immune cells via myriad mediators and receptors. These interactions generate action potentials that transmit pruritis and pain signals from the peripheral nervous system to the brain. Keratinocytes, the most abundant cell type in the epidermis, are key effector cells, triggering crosstalk with immune cells and sensory neurons to elicit pruritis, pain, and inflammation. Filaggrin expression by keratinocytes is reduced in atopic dermatitis, causing a weakened skin barrier and elevated skin pH. Fibroblasts are the main cell type in the dermis and, in atopic dermatitis, appear to reduce keratinocyte differentiation, further weakening the skin barrier. Fibroblasts and mast cells promote inflammation while dermal dendritic cells appear to attenuate inflammation. Inflammatory cytokines and chemokines play a major role in AD pathogenesis. Type 2 immune responses typically generate pruritis, and the type 1 and type 3 responses generate pain. Type 2 responses and increased skin pH contribute to barrier dysfunction and promote dysbiosis of the skin microbiome, causing the proliferation of Staphyloccocus aureus. In conclusion, understanding the dynamic interactions between cutaneous components in AD could drive the development of therapies to improve the quality of life for patients with AD.