may explain the epidemiological observation that patients with PN have increased risk of CAF-associated malignancies such as squamous cell carcinoma compared to patients with AD.34 Furthermore, fibroblast-derived secretory proteins WNT5A and periostin were found to interact with several neuronal receptors suggesting a novel fibroblast-neuronal axis. Activation of profibrotic responses and enrichment of fibroblast populations in PN skin relative to AD skin were also confirmed by Ma et al in a third independent single-cell RNA sequencing study.47 Treatment with nemolizumab, a monoclonal antibody targeting IL-31 receptor α (IL-31RA), reverses the pro-fibrotic transcriptomic and proteomic profiles in both the skin and serum.39,47,48 These findings strongly suggest a role of fibroblasts and mesenchymal dysregulation in the induction and maintenance of PN as well as their connection with the immune and neural axes, which is unique to PN compared to AD.
Psychodermatological Perspectives of PN
Chronic pruritus, the most defining characteristic of PN, along with unsightly skin lesions, bleeding, pain, sleep loss, and mental health symptoms, is associated with a negative impact on patients' quality of life (QoL).50-52 Several studies have investigated the impact of PN-associated itch on QoL with the Dermatology Life Quality Index (DLQI) being the most frequently used assessment tool.51,53,54 A systematic review and meta-analysis also found all studies to have moderate-to-severe pruritus and a very large or extreme effect on QoL.51
Pruritus worsens in the evening with the severity of nocturnal pruritus (NP) having a directly correlated impact on the severity of sleep disturbance.54,55 A recent study of 39 patients with PN found that the majority reported sleep disturbance to a great extent and that it correlated significantly with pruritus timing in the evening.56 Ständer et al further validated the Sleep Disturbance Numeric Rating Scale (SD NRS) in patients with PN.57 The SD NRS is a single-item patient-reported outcome (PRO) assessing day-to-day sleep disturbance in patients with pruritic conditions and has been previously validated in AD.58 Its use as a PRO for assessing PN impact on QoL in the clinic and in clinical trials remains to be determined.
In addition to its impact on QoL, PN also imparts an economic burden. A cohort study of 36 patients with PN by Whang et al found that when compared to controls, patients with PN had worse health performance, which they correlated to an average of 6.5 lifetime quality-adjusted life years (QALYs) lost per patient. This translated to an individual lifetime economic burden of $323,292 and a total societal burden of $38.8 billion.52
Psychiatric Conditions in PN
The intense pruritus of PN, as well as the disfiguring skin lesions, can have profound negative effects on the patient’s mental health. Likewise, stress and psychological factors can significantly impact the development and severity of PN. While etiology of PN has not been fully elucidated, neuronal sensitization to itch and the development of the itch-scratch cycle has been hypothesized as a simplified origin of the condition. In fact, PN is associated with neural sensitization disorders of pain.59 Nonetheless, there are significant interplays between dermatology, neurology, and psychiatry in the development and disease process.
Psychocutaneous conditions are those conditions, such as psoriasis, atopic dermatitis, or prurigo, in which psychological stress is a key element in causing exacerbations or flare-ups of the skin conditions.60 Another classifying term for prurigo is a psychophysiologic disorder, which is a skin condition that is inherently susceptible to psychological stress in disease precipitation or exacerbation.61
Patients with PN have higher rates of systemic illnesses (eg, autoimmune conditions) and mental health disease.62,63 Psychiatric conditions are significantly more prevalent in individuals with PN than in the general population.64,65 Those found more commonly in patients with PN include eating disorders, self-harm, attention deficit/hyperactivity disorder, schizophrenia, mood disorders, anxiety, and substance use disorders.13
Underlying psychiatric conditions can influence the patient’s perception of their disease; for example, a patient with comorbid major depressive disorder and pruritic cutaneous conditions might experience an increased sensation of itching.66 Stress and emotional tensions can contribute to worsening the itching sensation in pruritic conditions such as PN and lichen simplex chronicus.62
