Prurigo nodularis (PN) is a chronic skin condition characterized by intensely itchy, firm, raised lumps that can appear anywhere on the body. These dome-shaped nodules result from persistent scratching, rubbing, and picking at the skin. The primary cause is often considered idiopathic, meaning the exact trigger is unknown. PN is understood as a reaction pattern where multiple factors converge to create a complex, self-perpetuating cycle involving the neuro-immune-cutaneous system.
The Central Role of Nerve Hypersensitivity
The physiological engine driving Prurigo nodularis is an alteration in the skin’s nerve pathways, causing an exaggerated response to stimuli. Biopsies of affected areas frequently reveal an abnormal density of nerve fibers, particularly small, unmyelinated C-fibers, which transmit itch signals. These sensory neurons become hypersensitive (peripheral sensitization), causing them to fire signals more easily.
This heightened nerve sensitivity leads to hyperknesis, where a mild stimulus is perceived as an intense itch. The constantly firing nerves release neuropeptides, such as Substance P and Calcitonin Gene-Related Peptide (CGRP), which promote inflammation and nerve growth. The intense itch compels scratching, which damages the skin and causes the formation of firm nodules. This scratching reinforces nerve hypersensitivity, creating a vicious “itch-scratch-thicken” cycle.
Pre-existing Skin Conditions
Prurigo nodularis often begins due to an underlying dermatological issue that provides the initial itch trigger. These conditions compromise the skin barrier, allowing the neuropathic cycle to take root. Atopic dermatitis, a common type of eczema, is frequently associated with PN, sometimes present in over half of patients.
Atopic dermatitis causes chronic inflammation and dryness (xerosis), which lowers the itch threshold. When the skin barrier is damaged, irritants and allergens penetrate easily, initiating the inflammatory cascade and persistent itching. Other skin issues, including contact dermatitis or severe dry skin, can serve as the starting point. The mechanical trauma from scratching transforms the initial lesion into the fibrotic, nodular lesions of PN.
Systemic Diseases and Internal Associations
Prurigo nodularis frequently co-occurs with internal medical conditions that alter body chemistry or immune function. These systemic associations cause chronic, widespread pruritus, which acts as the primary trigger for scratching.
Chronic kidney disease, especially in its later stages, causes itch (uremic pruritus) due to the buildup of toxins the kidneys can no longer clear effectively. Liver diseases, such as chronic hepatitis C and cholestasis, are also associated with PN, as bile salts in the bloodstream can directly stimulate sensory nerves and induce intense itching.
Immune dysregulation seen in conditions like human immunodeficiency virus (HIV) infection and certain hematological malignancies, such as non-Hodgkin lymphoma, increases the risk of developing PN. In these cases, the internal disease creates a pro-inflammatory state that contributes to the chronic itch and the subsequent development of nodules.
The Influence of Psychological Factors
Psychological states do not cause Prurigo nodularis in isolation, but they play a role in modulating the intensity and persistence of the itch. A bidirectional relationship exists: mental health conditions can worsen PN, and the physical suffering of PN can exacerbate mental distress. Chronic stress, anxiety, and depression are common comorbidities that lower an individual’s itch threshold.
Anxiety and stress may trigger the release of hormones and neurotransmitters that influence the skin’s sensory nerves and inflammatory response. This makes the skin more reactive to minor stimuli, intensifying the urge to scratch and perpetuating the itch-scratch cycle. The relentless nature of the itch and the visible lesions lead to high rates of sleep deprivation, anxiety, and depression, making management more challenging.