Shared Mechanistic Pathways in Bullous Pemphigoid, Chronic Spontaneous Urticaria, Prurigo Nodularis, and Chronic Prurigo of Unknown Origin: Implications for Targeted Therapies

Abstract

Bullous pemphigoid, chronic spontaneous urticaria, prurigo nodularis, and chronic prurigo of unknown origin are distinct chronic skin diseases with a high disease burden and an ongoing need for safe and effective therapies. Advances in our understanding of disease mechanisms have highlighted convergent type 2-associated neuroimmune pathways that may contribute to chronic itch and skin lesions across these conditions. In bullous pemphigoid, autoantibody binding of two dermal–epidermal junction proteins followed by complement system activation shapes the local immune environment to favor T helper cell 2 polarization and perpetuation of type 2 inflammation. In chronic spontaneous urticaria, mast cell activation and downstream mediators, including type 2 cytokines, may contribute to amplification of inflammation and itch. In prurigo nodularis, chronically activated itch sensory neurons induce an itch-scratch cycle with T-cell activation in parallel to mast cell degranulation, resulting in neurogenic inflammation that sustains the itch-scratch cycle. The pathogenesis of chronic prurigo of unknown origin is not well understood, but evidence to date points to interactions between skin barrier defects and immune and neural dysregulation triggering T helper cell 2 polarization. In this review, we discuss the role of type 2 inflammation in bullous pemphigoid, chronic spontaneous urticaria, prurigo nodularis, and chronic prurigo of unknown origin, and how this understanding is currently translated into new targeted therapeutic options.

Key Points

Bullous pemphigoid, chronic spontaneous urticaria, prurigo nodularis, and chronic prurigo of unknown origin are itching disorders that impair quality of life and have unmet medical needs.

Type 2-skewed inflammation and related neuroimmune circuits appear to contribute, in various degrees, to signs and symptoms in each of these clinically distinct diseases.

Targeting drivers of type 2 inflammation is emerging as an effective approach to therapeutic intervention in these diseases.

Introduction

Bullous pemphigoid (BP), chronic spontaneous urticaria (CSU), prurigo nodularis (PN), and chronic prurigo of unknown origin (CPUO) are chronic skin diseases commonly encountered in dermatology practice. Patients often present with significant distress due to the shared symptom of intense itch, which carries a profound impact on their quality of life [1]. While underlying risk factors, pathophysiology, and clinical presentation are markedly different between these diseases, they are all characterized by a high symptomatic burden and a chronic course with frequent relapses and significant unmet needs. Recent developments in our mechanistic understanding of these diseases reveal similarities in their underlying pathophysiology, with type 2 inflammation-associated pathways contributing to disease initiation and/or amplification, as well as being consistently implicated in chronic itch, which in turn prompts novel therapeutic implications. In this review, we examine the physiological role of type 2 inflammation and its involvement in each condition, with an emphasis on whether this pathway represents a cause or a consequence of each disorder. In addition, we discuss how this recognition is translating into the use of targeted therapies to reduce disease burden and improve quality of life.

Physiological Role of Type 2 Inflammation

The type 2 immune response evolved to protect and repair epithelial tissues and is activated by default when the skin barrier is disrupted, which can be due to innate defects, multicellular pathogens (such as helminths), injuries, or other environmental insults [2]. During the type 2 response, multiple cytokines are released, triggering several pathways including differentiation of naïve T cells into T helper 2 (Th2) cells, class switching of B cells to produce immunoglobulin E (IgE), and recruitment and activation of effector cells (mast cells, eosinophils, basophils), with onset of type 2 inflammation [2, 3].

The main type 2 cytokines are interleukin (IL)-4, IL-13, IL-5, and IL-31, primarily produced by activated Th2 cells, but also by mast cells, eosinophils, and basophils [2]. Interleukin-4 and IL-13 are proinflammatory, driving recruitment and degranulation of effector cells [4–6]; they can also activate itch sensory neurons through IL-4 receptor alpha [7] and promote fibrosis and tissue repair [4, 5, 8]. In addition, IL-4 promotes Th2 differentiation, limits the development of T regulatory cells (Tregs) [9], and activates the B-cell class switch to IgE [10]. Interleukin-5 stimulates development, migration, activation, and survival of eosinophils [11]. Interleukin-31 acts as a potent pruritogen to elicit non-histaminergic itch [6, 11] and is also a pro-fibrotic cytokine [12, 13]; expression of IL-31 receptor alpha is upregulated by IL-4 stimulation [14].

Once the skin barrier injury is resolved, changes in the cytokine microenvironment are thought to turn the balance in favor of Tregs, which inhibit Th2 cells and limit inflammation [3, 9, 15]. However, if production of type 2 cytokines, especially of IL-4, continues, Tregs cannot overcome Th2 activation, and inflammation enters a self-amplifying loop, becoming chronic [3, 9]. As the immune system includes a limited number of effectors and response pathways, this self-amplifying loop can also be initiated independently of barrier disruption through direct activation of effector cells via high-affinity FcεRI receptors for IgE, via non-immunologic receptors by neuropeptides, complement anaphylatoxins, and other mediators, or through inherited defects of Treg activation [3, 9, 15].

Role of Type 2 Cytokines in Chronic Itch

Itch is a built-in component of the type 2 immune response, evolved to expel parasites by scratching. Skin sensory neurons express receptors for type 2 cytokines, which upon activation trigger the pruritic sensation [7]. Multiple cytokines released during mounting of type 2 inflammation, such as IL-4, IL-13, and IL-31, thymic stromal lymphopoietin, and others, are direct pruritogens [16]. In addition, IL-4 has been shown to induce sensitization of itch sensory neurons to respond to otherwise sub-threshold levels of other pruritogens [17]. By promoting Th2 proliferation and survival, IL-4 drives immune response amplification resulting in sustained itch and therefore is a central orchestrator of chronic itch (itch persisting ≥6 weeks) [6] (Fig. 1). However, chronic itch associated with skin conditions can also originate outside the skin as a result of various metabolic, neurologic, or autoimmune conditions, as well as cancers or primary neuropathy, all of which can induce activation of itch sensory neurons. Skin resident mast cells located in close vicinity to nerve endings express receptors for neuropeptides secreted by activated sensory nerve fibers [18]. Neuropeptides such as substance P were shown to act on mast cell neurokinin 1 and mas-related G-coupled receptor membrane X2 receptors and induce degranulation with release, among other mediators, of type 2 cytokines, thus triggering neurogenic skin inflammation, which further promotes neurogenic chronic itch (Fig. 1) [18–21].

Fig. 1.

Roles of type 2 cytokines in chronic itch. IL interleukin, IL-4Rα interleukin-4 receptor alpha, IL-31R interleukin-31 receptor, Th2 T helper cell 2, TSLP thymic stromal lymphopoietin, TSLPR thymic stromal lymphopoietin receptor

Overall, persistent over-expression of type 2 pruritic cytokines, regardless of initiation trigger, leads to chronic itch [16, 22], suggesting that skin diseases with chronic itch may benefit from therapeutic molecules targeted against type 2 cytokines. To date, several type 2 cytokine inhibitors have shown efficacy against chronic itch in phase III, randomized, placebo-controlled trials: the IL-4/IL-13 dual inhibitor dupilumab in atopic dermatitis (AD), PN, BP, and CSU [23–26]; the IL-31 inhibitor nemolizumab in AD and PN [27, 28]; and the IL-13 inhibitors tralokinumab and lebrikizumab in AD [29, 30], while other compounds for skin conditions associated with chronic itch are in various phases of clinical development.

Bullous Pemphigoid (BP)

Clinical Characteristics, Diagnosis, and Conventional Treatment

Bullous pemphigoid is an autoimmune blistering disease that usually affects patients aged 70 years and above and is associated with a substantial impact on quality of life and mental health, and a high economic burden [31, 32]. Bullous pemphigoid onset is often insidious, including a prodromal non-bullous phase with pruritus and erythematous, eczematous, or urticarial-type lesions and without tense blisters, followed, but not always, by a bullous phase, which can develop after months or years. With established disease, there are mostly tense blisters and erosions on erythematous, urticarial, or normal skin. Often, the clinical picture is diverse, encompassing multiple lesion types (erythema, hives or wheals, PN-like nodules, eczematous lesions), with or without tense blisters [33, 34]. The most common patient complaint is itch, resulting in difficulties in falling asleep and/or disrupted sleep [33, 35]. Approximately 40% of patients with BP present with comorbid neurological disease, including multiple sclerosis, Parkinson’s disease, epilepsy, stroke, or dementia [36–39]. Additionally, cardiovascular, metabolic, autoimmune, inflammatory conditions, and infections are frequent comorbidities, as certain treatments for these conditions can trigger BP development (e.g., treatment with gliptins, aldosterone antagonists, anticholinergic agents, dopaminergic agents, and immune checkpoint inhibitors) [39–41]. Diagnosis of BP is established based on the combination of the clinical presentation (including a comprehensive clinical assessment, evaluation of medical and medication history, comorbidities, patient-reported symptoms, functional status, physical exam) with direct immunofluorescence microscopy of a perilesional biopsy and detection of serum autoantibodies (Table 1) [36, 42].

Table 1.

BP, CSU, PN, and CPUO: diagnosis outline

Diagnosis	Clinical criteria	Clinic visit	Laboratory assessments
BP	• Tense blisters, erosions • Pruritic urticarial plaques • Variable non-bullous pictures, e.g., urticarial or eczematous lesions accompanied by pruritus	Medical history • Patient-reported symptoms and caregiver/family’s supportive narrative • Comprehensive medication history (to assess for potential drug triggers) • Comorbidities and overall functional status • Physical examination	• Perilesional skin biopsy for direct immunofluorescence • Lesional skin biopsy for histopathology (H&E stain) • Serum sample   o Indirect immunofluorescence on salt-split skin   o BP180 ELISA   o BP230 ELISA (when BP180 ELISA negative)
CSU	• Spontaneous appearance of daily or almost daily itchy hives with or without angioedema lasting >6 weeks • Each hive resolves within 24–36 hours with no residual lesion • Absence of fever, malaise, and joint/bone pain	• Provisional CSU diagnosis can be reached via an accurate history of hives occurrence, duration, characteristics, trigger factors, and other ± symptoms • Physical examination includes review of patient photo documentation (pictures of wheals and angioedema)	• Blood tests (CBC, differential blood count, CRP, antithyroid antibodies [antithyroid peroxidase antibodies], total IgE) • In some situations, it is important to exclude inducible urticaria by conducting a specific provocation test. Typically, hives appear only when the trigger contacts the skin and last <2 hours, except in cases of delayed pressure urticaria
PN	• Pruritus lasting ≥6 weeks • Firm, pruritic nodules • History and/or signs of repeated scratching, picking, or rubbing	• Thorough history and examination including review of medications and prior laboratory work • Assess severity: extent of lesions, pruritus intensity, disease burden • If necessary, assess the need for behavioral and emotional support for anxiety or depression	• May include CBC, liver, and renal function tests • Depending on risk factors, review of systems: thyroid function, diabetes assessment, HIV, and hepatitis B and C testing • Additional tests: work-up can be broad based on each patient’s unique medical history
CPUO	• Generalized/non-localized pruritus lasting ≥6 weeks with no identifiable primary rash and often no secondary skin lesions either • Exclusion of primary dermatologic or other underlying medical disorders (e.g., immunologic, systemic, neuropathic, infections, iatrogenic)	Medical history and physical examination • Timing, location, and duration of pruritus; medications and comorbidities (e.g., narcotic use); environmental factors	• CBC with differential and liver, renal, and thyroid function tests • Additional tests: biopsy recommended for any patient with a history of a skin lesion in a pruritic site or if suspicion for latent pruritic dermatosis is high because of history or risk factors   o If malignancy is suspected, refer for malignancy screening   o Refer for neurologic work-up if neurologic cause is suspected

BP bullous pemphigoid, CBC complete blood count, CPUO chronic prurigo of unknown origin, CRP C-reactive protein, CSU chronic spontaneous urticaria, ELISA enzyme-linked immunosorbent assay, H&E hematoxylin and eosin, HIV human immunodeficiency virus, IgE immunoglobulin E, PN prurigo nodularis

The first-line treatments in BP, depending on severity, are topical or oral corticosteroids (CS) [42]. In moderate and severe BP, CS are usually combined with potentially CS-sparing drugs, i.e., dapsone, doxycycline, azathioprine, and mycophenolate [42–44]. However, relapses are frequent, and many patients have contraindications due to associated comorbidities. Thus, alternate therapies are to be used either as monotherapy or in combinations, or to taper off CS when needed in BP [42].

Pathophysiology

Bullous pemphigoid development is associated with circulating autoantibodies against the BP180 (also termed type XVII collagen) and BP230 hemidesmosomal proteins, which anchor basal keratinocytes to the basement membrane. Immunoglobulin G (IgG) anti-BP180/BP230 autoantibodies trigger dermal–epidermal separation through complement system activation and chemotaxis of innate immune effectors such as eosinophils, basophils, neutrophils, macrophages, and mast cells [32, 36]; serum levels of anti-BP180 NC16A IgG correlate with disease activity [45]. Bullous pemphigoid histopathology is characterized by subepidermal blisters and eosinophil-rich or lymphocyte-rich infiltrates located at the dermal–epidermal junction, in the papillary dermis and perivascular [46, 47].

While complement activation is a key mechanism in BP, emerging evidence supports the contribution of complement-independent pathways to pathogenesis [47, 48]. Autoantibody production in BP is Th2 dependent [49], and several observations in vivo, in vitro, and in animal models support a role for type 2 immune dysregulation in BP pathogenesis. These include the elevated levels of Th2 cytokines in the serum, skin, and blister fluid of patients with BP [50, 51]; the significant upregulation of IL-4 and IgE responses in naïve T cells stimulated with BP180 antigen [52]; the elevated total serum IgE antibodies and the presence of serum IgE anti-BP180/BP230, as well as bound to FcεRI high-affinity receptors on eosinophils and mast cells [53–57]; the ability of non-complement-binding BP autoantibodies to induce blistering [58], and of IgE-BP180 complexes to induce degranulation of basophils (Fig. 2) [53]. Pathogenicity of IgE autoantibodies in BP is supported by observations of increased clinical severity in patients with BP with anti-BP180 IgE antibodies, and by case series of successful treatment with omalizumab, which inhibits the IgE binding to FcεRI [47, 59–61]. Additionally, TARC/CCL17 and PARC/CCL18 chemokines, which promote Th2 and B-cell responses, have been found to be upregulated in skin lesions and serum of patients with BP at levels correlated with disease activity [62–64], and transcriptomic and immunohistochemical studies have shown upregulation of the Janus kinase (JAK)-STAT pathway, signaling downstream of Th2 cytokines and chemokines, in lesional BP skin [65, 66].

Fig. 2.

Pathways involved in the pathogenesis of bullous pemphigoid. BTK Bruton tyrosine kinase, IgE immunoglobulin E, IgG immunoglobulin G, IL interleukin, IL-4Rα interleukin-4 receptor alpha, IL-5Rα interleukin-5 receptor alpha, IL-31R interleukin-31 receptor, JAK Janus kinase, MRGPRX2 mas-related G-coupled receptor membrane X, Th2 T helper cell 2, TSLP thymic stromal lymphopoietin, TSLPR thymic stromal lymphopoietin receptor

Itch Mechanisms in BP

Eosinophils and basophils are considered major cellular effectors in BP [50, 67]. Along with inducing dermal–epidermal separation through toxic granule proteins, eosinophil and basophil degranulation also releases pruritic and sensitizing cytokines such as IL-4, IL-13, and IL-31 [50, 67, 68]. Itch severity in BP was found to correlate with eosinophil and basophil counts in skin biopsies [68, 69], as well as with lesional levels of IL-13, IL-31, substance P, and other mediators [69]. The BP dermal infiltrate shows elevated levels of IL-4 and IL-13 [70], and IL-4 levels in blister fluid are increased compared with those in BP sera [71, 72]. These findings support a role for pruritogen type 2 cytokines in initiating and maintaining pruritus in BP, which occurs in parallel to the eosinophil/basophil role in blister development.

Emerging Type 2 Immune Response-Targeted Therapies in BP

Several type 2 immune response-targeted molecules have been evaluated to date in BP. Of these, based on results of a phase II/III, randomized, placebo-controlled clinical trial in patients with moderate-to-severe BP, the IL-4/IL-13 inhibitor dupilumab became the first US Food and Drug Administration-approved biologic (Table 2) [25, 73]. In a case series, the IL-13 inhibitor tralokinumab has been successfully used in BP [74]. In contrast, clinical trials targeting cytokine IL-5 (with mepolizumab) and its receptor IL-5 receptor alpha (with benralizumab) failed to prove efficacy. Omalizumab, which acts by reducing the IgE-mediated inflammation in BP, is sometimes used off-label, typically as adjunct or rescue therapy in refractory or steroid-intolerant BP [42, 60, 61, 73]. In a recent study, the use of JAK-STAT inhibitors in patients with BP was associated with reductions in inflammatory markers and disease activity, suggesting JAK inhibition as another potential targeted mechanism in BP [66]. Further studies are needed to understand the full efficacy benefits of approved targeted molecules, to explore other potential therapeutic targets in BP, and to identify biomarkers for treatment selection.

Table 2.

Targeted therapies currently in clinical development in BP, CSU, PN, and CPUO

	Targeted molecule/pathway	Therapeutic product	Randomized placebo-controlled clinical trial	Current stage	Key efficacy outcomes
BP	IL-4Rα (IL-4 and IL-13)	Dupilumab	BP ADEPT, phase II/III (NCT04206553)	Approved [25] (adult patients with BP)	The proportion of patients achieving sustained remissiona at week 36 was 18.3% with dupilumab and 6.1% with placebo The proportion of patients achieving a ≥4-point improvement from baseline in PP-NRS at week 36 was 38.3% with dupilumab and 10.5% with placebo [25]
CSU	Free IgE	Omalizumab	NCT01287117 and NCT01292473	Approved [97] (patients ≥12 years of age with CSU who remain symptomatic despite H1-antihistamine treatment)	Mean change from baseline in ISS7 (SD) at week 12 was -6.66 (6.28) with omalizumab 150 mg, -9.40 (5.73) with omalizumab 300 mg, and -3.63 (5.22) with placebo Mean change from baseline in HSS7 (SD) at week 12 was -7.78 (7.08) with omalizumab 150 mg, -11.35 (7.25) with omalizumab 300 mg, and -4.37 (6.60) with placebo [97]
	IL-4Rα (IL-4 and IL-13)	Dupilumab	CUPID Study A and Study C (NCT04180488)	Approved [25] (patients ≥12 years of age with CSU who remain symptomatic despite H1-antihistamine treatment)	Study A/C mean change (SE) from baseline in ISS7 at week 24 was -10.44 (0.92)/-8.50(1.39) with dupilumab and -6.02(0.94)/-6.13(1.38) with placebo Study A/C mean change (SE) from baseline in UAS7 at week 24 was -20.99 (1.77)/-15.61(2.62) with dupilumab and -11.95(1.81)/-11.27(2.61) with placebo [25]
	BTK	Remibrutinib	REMIX-1 (NCT05030311) and REMIX-2 (NCT05032157)	Approved [101] (adult patients with CSU who remain symptomatic despite H1-antihistamine treatment)	REMIX-1/REMIX-2 mean change (SE) from baseline in ISS7 at week 12 was -9.52 (0.34)/-8.95 (0.34) with dupilumab and -6.89 (0.47)/-5.72 (0.45) with placebo REMIX-1/REMIX-2 mean change (SE) from baseline in HSS7 at week 12 was -10.47 (0.40)/-10.47 (0.39) with dupilumab and -6.86 (0.55)/-6.00 (0.53) with placebo REMIX-1/REMIX-2 mean change (SE) from baseline in UAS7 at week 12 was -20.02 (0.72)/-19.41 (0.70) with dupilumab and -13.79 (0.98)/-11.73 (0.95) with placebo [101]
	KIT	Barzolvolimab	EMBARQ-CSU1 (NCT06445023) [107] and EMBARQ-CSU2 (NCT06455202) [108]	Phase III	Results from the phase III studies not yet available In the phase II study NCT05368285, mean change (SE) from baseline in UAS7 at week 12 with barzolvolimab 75 mg q4w/150 mg q4w/300 mg q8w was -17.06 (1.493)/-23.02 (1.416)/-23.87 (1.479) and with placebo was -10.47 (1.462) [106]
PN	IL-4Rα (IL-4 and IL-13)	Dupilumab	PN PRIME (NCT04183335) and PN PRIME2 (NCT04202679)	Approved [25] (adults with PN)	PRIME/PRIME2 proportion of patients with a ≥4-point reduction from baseline in WI-NRS at week 24 was 60.0%/57.7% with dupilumab and 18.4%/19.5% with placebo PRIME/PRIME2 proportion of patients with an IGA PN-S score 0 or 1 at week 24 was 48.0%/44.9% with dupilumab and 18.4%/15.9% with placebo [25]
	IL-31RA	Nemolizumab	OLYMPIA 1 (NCT04501666) and OLYMPIA 2 (NCT04501679)	Approved [130] (adults with PN)	OLYMPIA 1/OLYMPIA 2 proportion of patients with a ≥4-point reduction from baseline in PP-NRS at week 16 was 56.0%/49.0% with nemolizumab and 16.0%/16.0% with placebo OLYMPIA 1/OLYMPIA 2 proportion of patients with IGA 0 or 1 at week 16 was 26.0%/38.0% with nemolizumab and 7.0%/11.0% with placebo [130]
	Oncostatin M receptor (IL-31 and oncostatin M)	Vixarelimab	NCT03816891	Phase IIb randomized clinical trial	The proportion of patients achieving a ≥4-point reduction from baseline in WI-NRS at week 16 with vixarelimab high-dose/mid-dose/low-dose was 66.0%/61.7%/29.8% and 16.7% with placebo The proportion of patients achieving an IGA-PN score 0 or 1 at week 16 with vixarelimab high/mid/low-dose was 38.3%/29.8%/14.9% and 10.4% with placebo [132]
	JAK1	Povorcitinib	STOP-PN1 (NCT06516952) [134] and STOP-PN2 (NCT06516965) [135]	Phase III randomized, double-blind, placebo-controlled clinical trial (recruiting)	Not yet available
CPUO	IL-4Rα (IL-4 and IL-13)	Dupilumab	LIBERTY-CPUO-CHIC (NCT05263206) [147]	Phase III randomized, double-blind, placebo-controlled clinical trial (recruiting)	Not yet available
	IL-31	Nemolizumab	NCT07074977 [148]	Phase II (recruiting)	Not yet available
	JAK1	Abrocitinib	NCT05038982	Phase II open-label, non-randomized	Proportion of patients with a ≥4-point reduction from baseline in PP-NRS at week 12 was 60.0% [149]

BP bullous pemphigoid, BTK Bruton tyrosine kinase, CPUO chronic prurigo of unknown origin, CSU chronic spontaneous urticaria, HSS7 Hive Severity Score over 7 days [0–21], IGA PN-S Investigator’s Global Assessment for Prurigo Nodularis-Stage [0–4], IgE immunoglobin E, IL interleukin, IL-31RA interleukin 31 receptor alpha, IL-4Rα interleukin 4 receptor alpha, ISS7 Itch Severity Score over 7 days [0–21], JAK1 Janus kinase 1, KIT tyrosine-protein kinase KIT, OCS oral corticosteroids, PP-NRS Peak Pruritus-Numerical Rating Scale [0–10], PN prurigo nodularis, q4w every 4 weeks, q8w every 8 weeks, SD standard deviation, SE standard error, UAS7 Urticaria Activity Score over 7 days [0–42], WI-NRS Worst Itch-Numerical Rating Scale [0–10]

^aComplete remission defined as the achievement of complete remission and off OCS no later than week 16, absence of disease relapse from the completion of the corticosteroid taper to week 36, and absence of rescue therapy during the 36-week double-blind treatment period

Chronic Spontaneous Urticaria (CSU)

Clinical Characteristics, Diagnosis, and Conventional Therapy

The typical CSU clinical picture includes wheals that arise without identifiable triggers, are itchy, resolve within 24 h, and recur daily or nearly daily for more than 6 weeks, in the absence of fever, malaise, or bone/joint pain [75]. Approximately 90% of patients with CSU develop wheals and in 40% of cases wheals are accompanied by angioedema [76, 77], which may take longer (up to 36–48 h) to resolve [75, 77, 78]. All patients with CSU experience chronic itch, usually associated with sleep disturbance; owing to the unpredictability of episodes, anxiety and distress are common [79]. The most common comorbidities are atopic and autoimmune diseases and psychiatric disorders, mainly anxiety and depression [76, 77, 80, 81]. Chronic spontaneous urticaria considerably affects quality of life and is associated with significant healthcare resources and costs [82, 83]. A CSU diagnosis can be provisionally reached clinically, via an accurate history of the occurrence, duration, characteristics, and trigger factors of hives and associated symptoms [75], combined with a review of patient-provided photo documentation of wheals with or without angioedema. Laboratory tests are indicated to explore prognosis and treatment response biomarkers (Table 1) [75, 78, 84].

The current management of CSU includes antihistamines as first-line therapy, followed by added-on omalizumab as second-line therapy or cyclosporin as a third-line treatment; severe exacerbations may be treated with short-term CS [75]. However, in many patients, CSU remains inadequately controlled with current treatment options [83].

Pathophysiology

The etiology of CSU is not yet clarified, but autoimmunity is suspected, as up to 50% of patients have IgE auto-antibodies to self-antigens (such as thyroperoxidase, IL-24, double-stranded DNA, and others, yet the functional significance remains to be proven) and approximately 35% of patients have IgG autoantibodies against the IgE high-affinity FcεRI receptor or directly against IgE, with functional ability to activate basophils and mast cells [85, 86]. The presence of autoantibodies indicates that Th2-dependent B-cell activation contributes to the disease pathogenesis [87]. Mast cells and basophils are considered the key effectors responsible for the development of hives and angioedema [86, 88, 89]. The main mechanism leading to degranulation is currently thought to be immunologic, through cross-linking of FcεRI receptors by auto-IgG/IgE, but non-immunologic activation may also occur, with probable overlapping contribution [86]. The development of both wheals and angioedema is driven by perivascular mast cell release of histamine, tryptase, and leukotriene, which induce vasodilation, increase vascular permeability, and trigger inflammation [90, 91].

Chronic spontaneous urticaria histopathology is characterized by interstitial edema with dilated vessels and a perivascular mixed inflammatory infiltrate including Th1/Th2 lymphocytes, neutrophils, mast cells, basophils, and eosinophils [78, 82, 86, 92]. Although no clear histologic evidence for predominance of either Th1 or Th2 inflammation in CSU was found [84], dysregulated type 2 immune response pathways are thought to contribute to pathogenesis, as Th2 cells are present in lesional CSU skin [84, 93] and were shown to release higher amounts of IL-4 upon activation compared with healthy control cells (Fig. 3) [84]. In turn, IL-4 and IL-13 are thought to activate mast cells directly via cell surface IL-4 receptor alpha, resulting in increased FcεR1 expression [94, 95].

Fig. 3.

Pathogenic pathways in chronic spontaneous urticaria. BTK Bruton tyrosine kinase, IgE immunoglobulin E, IgG immunoglobulin G, IL interleukin, IL-4Rα interleukin-4 receptor alpha, IL-5Rα interleukin-5 receptor alpha, IL-31R interleukin-31 receptor, JAK Janus kinase, MRGPRX2 mas-related G-coupled receptor membrane X, Th1 T helper cell 1, TSLP thymic stromal lymphopoietin, TSLPR thymic stromal lymphopoietin receptor

Itch Mechanisms in CSU

Apart from its vasodilatory and proinflammatory role, histamine is a known pruritogen, triggering acute itch; however, the chronic itch in CSU is thought to be often only partially histamine related, and also mediated by type 2 immune dysregulation, which explains why some patients do not respond to therapy with antihistamines [22, 76]. Along with histamine, mast cell degranulation is a major source of IL-4, leading to activation and sensitization of non-histaminergic itch sensory neurons which, in turn, release neuropeptides that further perpetuate mast cell activation. Mast cells from CSU lesions were shown to overexpress receptors for neuropeptides [86]. In addition, basophils from CSU skin biopsies express the IL-31 pruritogen, which was found to amplify the IL-4 secretion from activated basophils, therefore amplifying itch and itch sensitization [86]. Chronic spontaneous urticaria lesional skin also exhibits elevated levels of thymic stromal lymphopoietin, another known type 2 pruritogen [16, 76, 93]. Altogether, it is thought that following the initial histamine-mediated development of wheals, angioedema, and acute pruritus, the ensuing cellular tissue infiltrate enters a self-perpetuating type 2 inflammatory loop, responsible for local chronic inflammation and chronic itch (Fig. 3) [86, 96].

Emerging Type 2 Immune Response-Targeted Therapies in CSU

The current understanding of effector cells and pathways involved in CSU has opened new therapeutic avenues (Table 2). Omalizumab, acting by targeting free IgE and therefore disrupting immunologic activation of mast cells and basophils, was the first biologic approved for patients with CSU refractory to antihistamines [97, 98]. However, complete resolution of CSU signs and symptoms with omalizumab is only achieved in one third to one half of patients [99]. Delayed or no response to omalizumab was linked to co-occurrence of IgG and IgE autoantibodies or to CSU caused by IgG autoantibodies [100]. In phase III randomized clinical trials in omalizumab-naïve/intolerant/incomplete responder patients with CSU uncontrolled with H1-antihistamines, blocking the IL-4/IL-13 signaling pathway with dupilumab led to improvements versus placebo in measures of itch and hives [26], leading to the approval of dupilumab in CSU [25]. Bruton tyrosine kinase is an intracellular signaling molecule acting downstream from the FcεR1 and B-cell receptors. Remibrutinib, a Bruton tyrosine kinase inhibitor, was recently approved for the treatment of adult patients with CSU who remain symptomatic despite H1-antihistamine treatment following two successful phase III, randomized, placebo-controlled clinical trials [101, 102]. Low total serum IgE is considered a marker for late or no response to omalizumab [103]. Both dupilumab and remibrutinib have shown efficacy independent of the baseline total serum IgE, which could be linked to their B-cell inhibitory effect with reduced production of both IgG and IgE autoantibodies [104, 105]. Another therapeutic avenue being pursued is targeted mast cell depletion with the c-kit inhibitor barzolvolimab, which met the primary endpoint in a phase II clinical trial [106] and is currently investigated in two parallel phase III trials (NCT06445203 and NCT06455202) [107, 108]. Anti-thymic stromal lymphopoietin tezepelumab did not reach statistical significance versus placebo in a phase IIb randomized clinical trial [109]. The anti-IL-5 mepolizumab was not associated with clinical or laboratory responses in patients with antihistamine-refractory CSU in a phase I trial [110], while benralizumab (anti-IL-5 receptor alpha) was discontinued after a phase IIb trial.

Prurigo Nodularis (PN)

Clinical Characteristics, Diagnosis, and Conventional Therapy

Patients with PN have a history of repeated scratching, picking, or rubbing, and complain of long-term (over 6 weeks) severe relentless itch and/or skin pain, burning or stinging, and sleep disruption [19, 111, 112]. Physical examination reveals firm, pruritic, nodular, or papular fibrotic lesions, usually distributed symmetrically and absent on body areas not reachable for scratching [113, 114]. Heterogeneous lesions comprising nodules, papules, excoriations, crusts, lichenification, scarring, and dyspigmentation can be present within the same patient [114]. Pruritic conditions (AD, renal/liver/neurologic disorders, or malignancies), as well as metabolic, cardiovascular, endocrine, and other diseases, are frequent comorbidities [115]. Prurigo nodularis is associated with markedly decreased quality of life and a high economic burden [116, 117]. Diagnosis of PN can usually be established clinically, based on an accurate history and examination, including a review of medications and prior laboratory work. A psychological evaluation may be necessary. Laboratory tests can be broad, based on each patient’s unique medical history (Table 1) [112, 114, 117].

In addition to addressing the causative neuropathy or comorbid pruritic condition, traditional approaches to PN management include CS, phototherapy, systemic antipruritic medication, and broad immunosuppressants, which may provide temporary symptomatic relief without curing the disease and are often associated with adverse events, resulting in a high unmet therapeutic need in PN [112].

Pathophysiology

Prurigo nodularis is thought to develop as a consequence of a chronic itch-scratch cycle established on a background of predominant type 2 immune dysregulation [118]. Initially, the itch can be neuropathic or a consequence of pruritic morbidities, but PN develops as a distinct disease, as uncontrollable chronic pruritus leads to scratching, eliciting an epithelial stress response in parallel to the itch sensory neuron-triggered dermal inflammatory response, with subsequent fibroblast activation and development of pruriginous hyperkeratotic fibrotic lesions [113, 114]. The main effector cells in PN are activated T cells, particularly Th2, and dermal perineural mast cells; these are activated following active sensory nerve fiber release of various neuromediators such as substance P, calcitonin gene-related peptide, nerve growth factor, and others. Neuropeptides released by itch sensory fibers promote neurogenic inflammation, vasodilation, mast cell degranulation, and nerve sensitization—effects additionally amplified by type 2 inflammatory signals resulting from mechanical stimulation by scratching (Fig. 4) [118–121]. Prurigo nodularis histopathology is characterized by hyperkeratosis, epidermal hyperplasia, intraepidermal nerve fiber hypoplasia with increased branching, and a dermal mixed infiltrate of lymphocytes, neutrophils, eosinophils, and macrophages [122].

Fig. 4.

Pathogenic pathways in prurigo nodularis. BTK Bruton tyrosine kinase, IL interleukin, IL-4Rα interleukin-4 receptor alpha, IL-5Rα interleukin-5 receptor alpha, IL-31R interleukin-31 receptor, JAK Janus kinase, MRGPRX2 mas-related G-coupled receptor membrane X, TSLP thymic stromal lymphopoietin, TSLPR thymic stromal lymphopoietin receptor

The role of dysregulated type 2 immune response in PN is well established [2, 114]. Though different ratios of several inflammatory profiles may contribute to PN pathogenesis in atopic/non-atopic skin or skin of color, skewing towards a type 2 inflammatory phenotype is considered the main disease mechanism, acting through the JAK-STAT pathway [2, 114]. Type 2 cytokines are increased in PN skin compared with healthy skin [123]; additionally, JAK1 is activated following stimulation of itch sensory neurons by IL-4 and is indispensable for chronic itch [7], while STAT3/STAT6 are upregulated in PN lesional skin [124, 125]. Activation of dermal fibroblasts in PN, with fibrosis and extracellular matrix production, is also considered to be Th2 dependent, mediated by pro-fibrotic effects of IL-4, IL-13, and IL-31 [2, 123].

Itch Mechanisms in PN

The dermal neurogenic inflammation in PN, apart from promoting development of fibrotic hyperkeratotic lesions, is associated with sustained release of pruritic and sensitizing type 2 cytokines such as IL-4, IL-13, and IL-31 [18–20]. Thus, in addition to the original neuropathic itch, the PN chronic itch is considered neurogenic, i.e., caused by the neurogenic dermal inflammation [125]. Patients with PN have elevated serum levels of IL-13 and IL-31, and the IL-4, IL-13, and IL-31 cytokines and their receptors are upregulated in skin nodules; itch intensity is correlated with IL-4 expression [126]. Another potent pruritogen in PN is periostin, a matricellular protein secreted by fibroblasts upon IL-4 and IL-13 stimulation [127], which was found deposited in patient dermis at levels that correlated with itch severity [128]. The characteristic heightened sensation of itch in PN is thought to be due to a major role of nerve sensitization by the IL-4 and IL-13 cytokines, which amplify neuronal responses to various other pruritogens [114, 129].

Emerging Type 2 Immune Response–Targeted Therapies in PN

Recent understanding of PN pathogenic pathways led to targeted approaches that specifically address immune dysregulation and neuroinflammation (Table 2). Thus, inhibition of IL-4/IL-13 signaling with dupilumab in patients with moderate-to-severe PN in a phase III, randomized, placebo-controlled clinical trial led to significant improvements in pruritus, skin lesions, and quality of life [24], and dupilumab became the first systemic therapy approved in PN [25]. This was followed by successful phase III randomized trials and the approval of the IL-31 receptor alpha antagonist nemolizumab [28, 130]. The IL-31/oncostatin M blocker vixarelimab showed promise in a phase II trial and is under further investigation [131, 132]. Other potential therapeutic compounds such as JAK inhibitors (upadatacitinib, povorcitinib, abrocitinib) have shown efficacy in case reports of recalcitrant PN [131] and the JAK1 selective inhibitor povorcitinib reduced pruritus and skin lesions in patients with PN in a phase II, randomized, placebo-controlled clinical trial [133] and is currently investigated in two parallel phase III trials (NCT06516952 and NCT06516965) [134, 135]. The next steps in PN management are efficacy assessment in different disease endotypes, and identification of biomarkers for personalized treatment.

Chronic Prurigo of Unknown Origin (CPUO)

Clinical Characteristics, Diagnosis, and Conventional Therapy

Chronic prurigo of unknown origin can develop at any age, although it is more common in the elderly [136]. Patients with CPUO experience episodes of moderate or severe itch occurring daily, usually accompanied by sensations of burning, tingling, and stinging [137]. Clinical examination may reveal xerosis, but no primary skin lesions, although lesions secondary to scratching may be present. Some patients have eosinophilia and moderately elevated serum IgE [137, 138]; T-cell and B-cell lymphopenia and decreased total IgG have also been reported [137]. Unlike BP, CSU, and PN, which all have distinct diagnostic criteria, diagnosis of CPUO is still evolving. Currently, CPUO is an exclusion diagnosis for pruritus lasting longer than 6 weeks in which no underlying cause is identified after a systemic evaluation, and when overlying skin changes are not present or are not diagnostic on visual or histologic examination (Table 1) [136, 139]. The current management of CPUO is symptomatic and relies on topical and systemic CS, antihistamines, phototherapy, neuromodulators such as gabapentinoids, and broad immunosuppressors.

Pathophysiology

The pathophysiology of CPUO is unclear, but it appears to involve age-related skin barrier defects overlapping with neural and immune dysfunction [140, 141]. The presence of xerosis suggests a loss of skin barrier function, which in turn may trigger Th2 polarization; this hypothesis is supported by the finding that Th2 cells are enriched in CPUO skin [142]. Additionally, histopathologic examination of skin biopsies in patients with CPUO showed dermal Th2 lymphocytic and sometimes eosinophilic infiltrate [138, 142]. A recent study reported increased plasma levels of type 2 cytokines and increased expression of protein drivers of Th2 polarization in patients with CPUO with elevated IgE (>100 kU/L) and absolute eosinophil count (>300 cells/μL) compared with patients with CPUO with normal IgE and eosinophil counts [143].

Itch Mechanisms in CPUO

Interleukin-4-activated Th2 cells are the main source of the IL-31 pruritic cytokine [3, 144]; in line with the finding of a dermal Th2 infiltrate in CPUO, IL-31 has been found significantly elevated in patients compared with healthy subjects [145]. Interleukin-33, a strong amplifier of type 2 immune responses, was also found to be systemically elevated in patients with CPUO [141]. Recently, IL-33 was shown to promote chronic itch by directly acting on itch sensory neurons in a mouse model of aged skin with dry skin mirroring CPUO, suggesting a particular role for IL-33 in CPUO pathogenesis [141]. In addition, expression of mast cell mas-related G-coupled receptor membrane X2 receptor was found significantly elevated in patients with CPUO, suggesting the non-immunologic activation of mast cells as a potential pathogenic mechanism [146].

Emerging Type 2 Immune Response-Targeted Therapies in CPUO

Based on current knowledge, targeted therapies against type 2 cytokines are thought to be able to interfere with the neuroimmune dysregulation in CPUO (Table 2) [141, 145]. Proof-of-concept trials are ongoing for the IL-4/IL-13 antagonist dupilumab (phase III, NCT05263206) [147] and the IL-31 antagonist nemolizumab (phase II, NCT07074977) [148]. The JAK inhibitor abrocitinib has shown promising results in a phase II clinical trial [149], but results in larger randomized clinical trials are needed.

Discussion

As our understanding of the intricate mechanisms underlying the pathogenesis of BP, CSU, PN, and CPUO continues to evolve, it is becoming increasingly evident that despite their differences, they share some fundamental biological pathways. Type 2 inflammation is emerging as a key driver in the pathogenesis of these diseases [2, 4, 150]; this is further supported by results from clinical trials targeting the type 2 inflammatory pathway, which demonstrate efficacy on both signs and symptoms.

Itch is a highly evolutionarily conserved sensation and, consequently, chronic itch is a common pathologic feature of many skin diseases, including BP, CSU, PN, and CPUO. Chronic itch, independently of the impact of associated skin lesions, has a marked negative effect on quality of life, and therefore raises an important need for therapeutic solutions [1, 151, 152]. Recent advances in understanding the role of interactions between epidermal barrier, neural, and immune pathways in producing the itch sensation revealed a prominent role for type 2 immune responses in the pathogenesis of chronic itch across different clinical entities [2, 15–18]. Several findings have direct implications on future therapeutic approaches, such as the fact that chronic itch, even if occurring in conditions associated with histamine release, is mostly non-histaminergic [151, 152]; that type 2 cytokines, and especially IL-4, can activate and sensitize itch sensory neurons to amplify responses to other pruritogens [17, 129, 151]; and that type 2 cytokines can be released in a positive feedback loop in conditions of sustained effector cell activation, regardless of the immune, non-immune, or neural nature of activation signals [22, 151, 153] (Fig. 1).

Beyond sharing chronic itch as a symptom, activation of effector cells with degranulation is a common mechanism contributing to skin lesion formation in these skin conditions. The different skin compartments where degranulation takes place, eosinophil/basophil/mast cell degranulation at the dermal–epidermal junction in BP, dermal perivascular mast cell and basophil degranulation in CSU, and dermal perineural mast cell/eosinophil degranulation in PN, explains the nature of the skin lesions and differences in the nature and quality of itch between these conditions. Apart from direct tissue injury by toxic granules, effector degranulation also releases type 2 cytokines with proinflammatory actions, contributing to local cellular infiltration and sustaining chronic inflammation.

Conclusions

Some already available results from randomized clinical trials support the potential of targeted immunomodulators against type 2 cytokines/receptors to provide itch and/or skin lesion relief in BP, CSU, PN, and CPUO. Therapies that are available currently or in development to target type 2 inflammation at various nodes in the inflammatory pathway include cytokine production and signaling, immune cell trafficking and activity, inflammatory mediator production, and stromal tissue responses. Further data from randomized trials on efficacy on signs, symptoms, or both, and safety are needed to select the type 2 immune inhibitors suitable for use in BP, CSU, PN, and CPUO. Given the chronic nature of these conditions, long-term safety of treatment is an important consideration, as are patient age, comorbidities, and ongoing medication. In parallel, characterization of disease endotypes and biomarkers will facilitate optimal therapy–patient alignment with the objective of optimizing patient outcomes.

Funding

This research was funded by Sanofi and Regeneron Pharmaceuticals Inc. The ADVENT program is funded and facilitated by Sanofi and Regeneron Pharmaceuticals Inc.

Declarations

Conflict of interest

Enno Schmidt received research funding from Admirx, Almirall, Alpine Immune, Argenx, AstraZeneca, Bayer, Biotest, CSL, Dompé, Euroimmun, Fresenius Medical Care, Incyte, Pharmaxis, and Sanofi and is a speaker for and/or received consulting fees from AbbVie, Argenx, AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Fresenius Medical Care, Janssen, and Sanofi. Marta Ferrer Puga received research funding from the Carlos III Health Institute (ISCIII), Novartis, and Thematic Networks for Cooperative Research Centres; and is a speaker for and/or received consulting fees from Celldex, Celltrion, FAES, Genentech, Menarini, MSD, Novartis, Regeneron Pharmaceuticals Inc., Sanofi, and Uriach. Brian S. Kim is Chair of the Scientific Advisory Board for Alys Pharmaceuticals; co-founder of Attu Therapeutics, Neurommune Therapeutics; Data Safety Monitoring Committee member for AbbVie and Advarra; reviewer for Almirall, Anvia Therapeutics, Atlas Venture, Bain Capital, Cara Therapeutics, Catalys Pacific, Clexio Biosciences, Elanco, Eli Lilly, Escient Pharmaceuticals, Evommune, Galderma, General Atlantic, Gilead Sciences, Goldman Sachs Life Sciences, Guidepoint Global, and Korea US Collaborative Research Fund; steering committee member for LEO Pharma; consultant for Medicxi, Monte Rosa Therapeutics, Neurocrine Biosciences, Novartis, OrbiMed, Pfizer, Quilt Bio, Recludix Pharma, Regeneron, ResearchHub Foundation, Sanofi, Schrödinger, Septerna, Triveni Bio, and Vida Ventures; scientific advisory board member for Attovia Therapeutics, Cell Reports Medicine, Neurocrine Biosciences, and Triveni Bio; editorial board member for the Journal of Allergy and Clinical Immunology; stockholder at ABRAX Japan, Alys Pharmaceuticals, Locus Biosciences, Recens Medical, and Triveni Bio; and received research grants from Eli Lilly and Triveni Bio. Eric L. Simpson received grants or served as principal investigator from/for AbbVie, Acrotech, Amgen, Arcutis, ASLAN, Castle, Dermavant, CorEvitas, Dermira, Eli Lilly, Incyte, Pfizer, Regeneron, Sanofi, Target, and VeriSkin; and received personal fees from AbbVie, Aclaris Therapeutics, Amgen, Arcutis, Astria Therapeutics, Attovia Therapeutics Inc., Bambusa Therapeutics Inc., Castle, CorEvitas, Dermira, Eli Lilly, Evommune, FIDE, Impetus Healthcare, Incyte, Inmagene Biopharmaceuticals, Innovaderm Recherches/Indero, Janssen, LectureLinx (LLX), LEO, Numab Therapeutics AG, Pfizer, Recludix Pharma, Regeneron, Roche Products Ltd, Sanofi, and Sitryx Therapeutics.

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All authors provided critical feedback on the manuscript, approved the final manuscript for submission, read and approved the final version, and are accountable for the accuracy and integrity of the manuscript.