Neuroimmune Parallels in Atopic Dermatitis and Prurigo Nodularis

Atopic dermatitis (AD) is a chronic inflammatory skin condition characterized by severe pruritus, skin barrier disruption, and immune dysregulation.¹ Prurigo nodularis (PN) is another chronic inflammatory skin condition characterized by severe pruritus, sharing key pathological and clinical features with AD.² Both conditions are perpetuated by the itch-scratch cycle, highlighting the shared role of chronic inflammation.³ Type 2 inflammation, specifically, is increasingly recognized as the central driver of AD and PN, with minor differences in key mediators existing between conditions.^3,4,5Patients with these conditions suffer from similar symptoms, including severe itch, decreased quality of life (QoL), sleep disturbance, and mental health disease.^2,6 This article will discuss the overlapping pathophysiological and clinical features of AD and PN, including shared therapeutic options and clinical pearls for clinicians.  

CLINICAL AND PATHOPHYSIOLOGIC OVERLAP

AD presents in age-dependent distributions of erythematous plaques with varying degrees of papules, scaling, crusting, and edema. PN may result from AD or independently in the majority of cases and presents as hyperkeratotic, fibrotic nodules, papules, or plaques on the extensor surfaces of the extremities and trunk.^2,7,8 Excoriations, hemorrhagic crusting, and lichenification result from chronic scratching in both conditions, with post-inflammatory pigmentary changes during healing of lesions.^7,8 Both conditions are intensely pruritic and driven by the itch-scratch cycle and underlying Type 2 inflammation. Elevated expression of the inflammatory mediators IL-4, IL-13, and IL-31 is common to both conditions and results in increased acute itch sensation and modulation of peripheral nerve fibers, leading to peripheral and central sensitization and hyperkinesis.^4,9

There are key differences in the location of pathology, with the majority of the pathology located in the dermis in PN, while in AD epidermal barrier dysfunction is a key driver of pathology. There is also significant fibrosis in PN.^10,11 In PN, dermal periostin, oncostatin, nerve growth factor (NGF), matrix metalloproteinases, IL-1𝛽, IL-1𝛼, and insulin-like growth factors and downregulation of collagen VI are more pronounced than in AD.^10,12,13 This suggests that PN patients experience higher levels of cutaneous neural dysregulation than AD patients.¹⁰ In both conditions, dysbiosis of the skin microbiome driven by S. aureus colonization further contributes to an overactive Th2 inflammatory response by production of virulence factors—such as proteases, toxins, and superantigens.^14,15,16

Beyond cutaneous symptoms, AD and PN result in significantly decreased QoL and are associated with increased incidence of mental health disorders, including depression and anxiety. Severe pruritus and visible lesions lead to social withdrawal, low self-esteem, and disrupted sleep and daily functioning.^2,17,18,19 Furthermore, both conditions commonly coexist with differing comorbidities. In AD, comorbidities cluster around allergic diseases (asthma, atopic march),^20,21whereas in PN, comorbidities include systemic diseases (renal, hepatic, metabolic, HIV and psychiatric disorders).^22,23These overlapping yet distinct mechanisms shape disease presentation, severity, and symptom burden, highlighting the need for targeted therapies to disrupt the itch-scratch cycle and restore barrier function.

THERAPEUTIC CONVERGENCE

The therapeutic landscape of AD and PN is converging, with overlapping use of biologics, Janus kinase (JAK) inhibitors, and conventional therapies that target shared type 2 and neuroimmune pathways. Both conditions respond to biologics blocking type 2 cytokines. Dupilumab (anti-IL-4Rα; inhibits IL-4/IL-13 axis) and nemolizumab (anti- IL-31RA) are the only FDA-approved biologics for both AD and PN in adults.^24,25 Both demonstrated efficacy in reducing itch and skin lesions in phase 3 trials.²⁶ Two other IL-13 blockers, tralokinumab and lebrikizumab, are currently only approved in AD.^4,27,28

JAK inhibitors are small molecules that block intracellular signaling downstream of multiple cytokine receptors, thereby modulating inflammatory and pruritic pathways. The oral JAK1 inhibitors upadacitinib and abrocitinib are only approved for use in AD.²⁹ Off-label use, however, demonstrated efficacy in PN.^30,31 Currently, a new JAK1 inhibitor, povorctinib, is undergoing phase 3 trials for PN.³²

Other therapies used in both AD and PN for many decades include topical corticosteroids, topical calcineurin inhibitors (such as tacrolimus and pimecrolimus), and topical JAK inhibitors for limited disease. For more extensive disease, phototherapy, immunosuppressants (such as methotrexate and cyclosporine), and drugs attenuating the neural sensitization (such as GABAergic drugs, kappa opioid agonists, and mu opioid antagonists) can be used, but all have limited efficacy and/or significant adverse effects.^33,34

CONCLUSION

Although AD and PN are distinct conditions, they are linked by shared type 2 and neuroimmune pathways that drive chronic itch, inflammation, and skin barrier dysfunction. Recognizing these overlaps helps clinicians apply therapeutic advances across both diseases, from biologics and JAK inhibitors to conventional agents. Biologic treatments, specifically, have undoubtedly reshaped how AD and PN are treated. However, differences between AD and PN support more targeted, patient-centered care.

AT A GLANCE

• Shared mechanisms: Both AD and PN are driven by type 2 and neuroimmune inflammation, leading to chronic itch.
• Therapeutic overlap: Biologics (dupilumab, nemolizumab) are effective across both diseases. Nemolizumab is currently the most rapid and effective treatment for PN, while dupilumab seems to cover different phenotypes and comorbidities of atopy better than nemolizumab. However, there are other therapies that are approved in only one disease or the other.
• Clinical impact: Early recognition and systemic treatment can disrupt the itch-scratch cycle, improve QoL, and reduce morbidity.

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