Prurigo Nodularis: Symptoms, Types, Causes and Treatment

Prurigo nodularis (PN) is a chronic, intensely itchy skin disorder that can have a major impact on a person’s daily life and well-being. Recognized for its hallmark nodules and relentless itch, PN is a complex condition that has long frustrated patients and clinicians alike. Recent research, however, is shedding light on its pathophysiology, associated diseases, and evolving treatment options. In this comprehensive article, we will explore the key symptoms, types, underlying causes, and current as well as emerging treatments for prurigo nodularis.

Symptoms of Prurigo Nodularis

Living with prurigo nodularis can be an exhausting experience, as the symptoms are not only visible but also deeply uncomfortable. The condition is marked by the appearance of multiple, intensely itchy nodules that often lead to an unending itch-scratch cycle, which can significantly impair sleep and quality of life. Recognizing these symptoms early is crucial for timely intervention and better management.

Symptom	Description	Impact	Source(s)
Nodules	Firm, hyperkeratotic, dome-shaped papules or nodules, often excoriated	Visible disfigurement	1,2,4,14
Pruritus (itch)	Severe, persistent itch often described as unbearable	Sleep disturbance, reduced QoL	2,3,4,14
Symmetrical distribution	Lesions commonly appear on extensor surfaces and trunk	Diagnostic clue	1,4,6
Lichenification	Thickened, leathery skin from repeated scratching	Chronic skin changes	6,9

Table 1: Key Symptoms

Hallmark Features

The most recognizable feature of PN is the development of firm, hyperkeratotic nodules that may number from a few to hundreds. These nodules are usually symmetrically distributed and predominantly affect the extensor surfaces of the arms, legs, and trunk, though they can occur anywhere except the face and mucous membranes 2,4,14.

The Itch-Scratch Cycle

Intense pruritus is the defining symptom of PN. The urge to scratch is often overwhelming, leading to repeated trauma to the skin, which in turn perpetuates the formation of new nodules and further itching—a phenomenon known as the itch-scratch cycle 2,3,6. This cycle can severely disrupt sleep and daily functioning.

Other Associated Symptoms

• Lichenification: Chronic scratching thickens the skin and makes it appear leathery 6,9.
• Excoriations and Scarring: Repeated scratching often results in open sores, bleeding, and secondary infections.
• Psychological Impact: The constant itch and visible skin changes can lead to social withdrawal, anxiety, and depression 3,10.

Types of Prurigo Nodularis

Not every case of prurigo nodularis is the same. PN can be classified into subtypes based on clinical presentation, underlying diseases, and patient demographics. Understanding the different types is essential for personalized management and for recognizing associated conditions.

Type	Distinguishing Features	Associated Conditions	Source(s)
Classic PN	Multiple, symmetrical, hyperkeratotic nodules	Atopic dermatitis, systemic diseases	4,6,10
Early-onset PN	Onsets in youth, often with atopy	Atopic diathesis	10
Late-onset PN	Onsets in older age, non-atopic	Systemic/neurologic disease	10
Chronic Prurigo	Broader category including nodular, papular, plaque, linear types	Variable	7

Table 2: Types of Prurigo Nodularis

Classic Prurigo Nodularis

This is the most common form, characterized by multiple, firm, itchy nodules located symmetrically on the extensor surfaces and trunk 4,6. It often evolves in adults but can occur at any age.

Early-Onset vs. Late-Onset PN

• Early-Onset PN: Typically arises in childhood or young adulthood and is frequently associated with a history of atopic dermatitis or other allergic conditions 10.
• Late-Onset PN: More common in older adults, this type is less likely to be linked with atopy and more often associated with systemic or neurologic diseases 10.

Chronic Prurigo and Subtypes

PN is technically a subtype of chronic prurigo (CPG), a group of disorders unified by chronic pruritus and scratch-induced lesions. Other subtypes include papular, plaque, and linear forms. Nodular prurigo (PN) is the most prevalent and severe 6,7.

Disease Variability

Patients may present with:

• Localized or generalized nodules
• Variable nodule size and number
• Differences in underlying comorbidities (e.g., atopic vs. non-atopic, presence of systemic disease) 7,10

Causes of Prurigo Nodularis

The exact cause of PN remains elusive, but it is increasingly recognized as a complex disorder involving neuroimmune interactions, genetic predisposition, and an array of trigger conditions. Identifying underlying causes and associations is critical for effective management.

Cause/Association	Mechanism or Link	Example Conditions	Source(s)
Chronic pruritus	Persistent itch leads to scratching, nodule formation	CKD, hepatic disease	6,9,10
Neuroimmune dysfunction	Altered nerve fibers and neuropeptide signaling	Increased NGF, Substance P	2,5,9,14
Dermatologic diseases	Underlying skin conditions	Atopic dermatitis, xerosis	1,10
Systemic illnesses	Systemic triggers for chronic itch	Diabetes, renal failure	10
Neurologic/psychiatric	Contribute to itch perception or scratching behaviors	Depression, anxiety	1,10
Infectious diseases	Pruritus linked to infection or immune activation	HIV, hepatitis C	10

Table 3: Causes and Associations

Chronic Pruritus as the Root

Most cases of PN begin with chronic, severe itching. The relentless scratching that follows leads to skin damage and nodule formation. This cycle can be triggered by a wide range of underlying conditions 6,9.

Neuroimmune and Molecular Factors

Recent studies highlight the role of reduced intraepidermal nerve fiber density, increased nerve growth factor, and elevated levels of neuropeptides such as substance P and calcitonin gene-related peptide 2,5,8,9. These changes create a “sensitized” skin environment that amplifies the itch sensation.

• Type 2 Inflammation: Some patients show evidence of Th2-skewed immune responses, especially those with higher eosinophil counts or atopic backgrounds 8.

Associated Diseases and Risk Factors

PN is often linked to:

• Dermatologic disorders: Atopic dermatitis, psoriasis, xerosis cutis 1,10.
• Systemic diseases: Diabetes mellitus, chronic kidney disease, liver disease, thyroid disorders 10.
• Neurologic and psychiatric conditions: Depression, anxiety, ADHD, schizophrenia, substance use disorders 10.
• Infections: HIV, hepatitis B and C, Helicobacter pylori 10.
• Malignancy: Higher risk of non-Hodgkin lymphoma 10.

Demographics and Prevalence

• PN is relatively rare, affecting an estimated 72 per 100,000 adults in the US (likely underreported) 10.
• Most commonly diagnosed in middle-aged to older adults, with a female predominance 4,10.

Importance of Identifying Underlying Causes

Because PN can be a manifestation of other systemic or dermatologic diseases, a thorough workup is recommended. Screening for chronic diseases, infections (especially HIV), and mental health conditions is vital in patients with newly diagnosed PN 1,10.

Treatment of Prurigo Nodularis

Managing prurigo nodularis is challenging due to its stubborn nature and the limited effectiveness of traditional therapies. However, advances in understanding PN’s pathophysiology are driving the development of new, targeted treatments. A multimodal, patient-centered approach remains the cornerstone of care.

Treatment	Modality/Target	Typical Use	Source(s)
Topical corticosteroids	Anti-inflammatory	First-line, mild-moderate	2,13,14
Capsaicin	Depletes neuropeptides (Substance P)	Refractory localized itch	2,11,13
Calcineurin inhibitors	Immune modulation	Steroid-sparing, sensitive areas	2,13
Phototherapy	Immunosuppressive UV light	Widespread disease	2,6,13
Systemic agents	Gabapentinoids, antidepressants, immunosuppressants	Severe/refractory cases	2,6,13
Biologics	Targeted immunomodulation (e.g., IL-4/IL-13)	Emerging, moderate-severe	5,7,12
Novel targets	Opioid, neurokinin-1, IL-31 receptor inhibitors	Clinical trials	2,6,7

Table 4: Treatment Strategies

First-Line and Topical Therapies

• Topical corticosteroids: Reduce inflammation and itch, commonly used as first-line therapy 2,13,14.
• Capsaicin cream: Shown to effectively reduce itch and help heal nodules by depleting substance P; requires frequent application and may cause burning sensation initially 2,11,13.
• Calcineurin inhibitors: Useful for steroid-sparing management, especially on the face or intertriginous areas 2,13.
• Topical vitamin D analogs (e.g., calcipotriol): Sometimes beneficial 13.

Phototherapy

Ultraviolet (UV) therapy (narrowband UVB or psoralen-UVA) can reduce inflammation and pruritus, particularly for patients with widespread or recalcitrant disease 2,6,13.

Systemic Treatments

For moderate-to-severe or treatment-resistant cases:

• Gabapentinoids (e.g., pregabalin): Target neuropathic itch pathways 2,6,13.
• Antidepressants (e.g., amitriptyline, paroxetine): Useful for the neuropathic component and comorbid mood disorders 13.
• Immunosuppressants (e.g., cyclosporine, methotrexate): Can suppress immune-mediated inflammation but have significant side effects 6,13.
• Thalidomide: Shown to be effective but limited by neurotoxicity and other adverse effects 13.

Biologics and Novel Therapies

• Dupilumab: The first systemic biologic approved by the FDA and EMA for PN, blocking IL-4 and IL-13 signaling. Clinical trials have shown significant improvement in itch and nodule count 7,12.
• Other biologics in trials: Nemolizumab (IL-31RA inhibitor), vixarelimab, barzolvolimab (mast cell inhibitors), and JAK inhibitors (ruxolitinib, abrocitinib) are promising new options 5,7.
• Opioid and neurokinin-1 receptor antagonists: Address neuroimmune mechanisms of itch, with ongoing clinical studies 2,6,7.

Multidisciplinary Approach

Effective management of PN often requires:

• Screening and treating underlying systemic or psychiatric conditions
• Patient education regarding the chronic nature of PN
• Psychological support and sleep hygiene interventions 3,10

Treatment Challenges

• Many patients are recalcitrant to standard therapies
• Relapses are common after discontinuation of treatment (e.g., capsaicin)
• Side effects and monitoring requirements limit long-term use of immunosuppressive agents 6,13,14

Conclusion

Prurigo nodularis is a complex, chronic skin disease where severe itch and nodular lesions significantly disrupt quality of life. Advances in research are bringing hope through novel therapies, but management remains challenging and requires a comprehensive, individualized approach.

Key Takeaways:

• PN presents as intensely pruritic, hyperkeratotic nodules, most often on the extremities and trunk.
• It is a subtype of chronic prurigo and can be classified by age of onset, atopy, and underlying conditions.
• Causes are multifactorial, involving neuroimmune dysfunction and associations with dermatologic, systemic, neurologic, and psychiatric diseases.
• Treatment is multimodal, starting with topical agents and phototherapy, and escalating to systemic therapies and emerging biologics for severe or refractory cases.
• New targeted treatments such as dupilumab and IL-31 inhibitors are changing the landscape for PN patients.
• Comprehensive care includes screening for underlying diseases and addressing mental health and quality of life concerns.

Prurigo nodularis is finally coming into focus, with research-driven care offering new avenues for relief and a better future for those affected.