Prurigo Nodularis


Article Author:
Tessa Mullins
Poonam Sharma


Article Editor:
Sidharth Sonthalia


Editors In Chief:
Bonnie Franckowiak


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes


Updated:
6/5/2019 11:50:47 AM

Introduction

Prurigo nodularis is a chronic disorder of the skin that is classically seen as multiple, firm, flesh to pink colored nodules commonly located on the extensor surfaces of the extremities. The lesions are typically pruritic and can occur in any age group. It is commonly associated with another disease such as atopic dermatitis or chronic pruritus. The diagnosis is clinical. Antihistamines, behavioral changes, topical corticosteroids, intralesional corticosteroids, as well as systemic therapies for extreme cases, treat prurigo nodularis.[1][2][3][4]

Etiology

The etiology of prurigo nodularis is unknown. It is uncertain how the itch-scratch cycle plays a role and whether the lesions are present before the pruritus or the pruritus causes the lesions. Prurigo nodularis is accompanied by long-standing pruritus and thought to develop as a reaction to repeated scratching in patients with chronic prurigo from various etiologies including dermatological, systemic, infectious, and psychiatric[5][6]. Neuronal proliferation, small fiber neuropathy, eosinophils, and mast cells play a role in the production of pruritus, although the exact mechanism has not yet been established [4]

Epidemiology

The incidence of prurigo nodularis is unknown. A majority of patients with prurigo nodularis present between ages 51 and 65 years, though several cases in other age groups have also been described[5][7]. It seems to be more frequent and more intense in females[8]. It is seen as one of the clinical presentations of adult-onset atopic dermatitis.[9]In HIV positive patients, prurigo nodularis s predictive of advanced immunosuppression[10].

Pathophysiology

The pathophysiology of prurigo nodularis has been debated. Some studies have shown an increased number of nerves in the papillary dermis which may suggest a neurocutaneous component. Nerve growth factor (NGF) and its receptor, tyrosine receptor kinase A (TrkA), are overexpressed in prurigo nodularis lesions. They may also be associated with the increased release and accumulation of neuropeptides, such as substance P and calcitonin gene-related peptide[11]. The role of helper T cytokines, T helper 1 and T helper 2, have also been studied in the pathogenesis of prurigo nodularis using the signal transducers and activators of transcription (STAT) 1, 3, and 6. In every case examined but three, the entire epidermis stained with anti-pSTAT 6, a marker for the Th2 cytokines interleukin (IL)-4, IL-5, and IL-13. These findings suggest that Th2 cytokines play a principal role in the pathogenesis of prurigo nodularis.[12] 

Histopathology

Lesions of prurigo nodularis under histopathology can show thick, orthohyperkeratosis, irregular epidermal hyperplasia, and pseudoepitheliomatous hyperplasia. Focal parakeratosis with irregular acanthosis diminished nerve fiber density and a nonspecific dermal infiltrate containing lymphocytes, macrophages, eosinophils, and neutrophils may also be seen on histology for prurigo nodularis lesions. Histology can play an important role in diagnosing prurigo nodularis vs. lichen simplex and hypertrophic lichen planus. Lesions of lichen simplex are less likely to have pseudoepitheliomatous hyperplasia or nerve fiber thickening; however, it does not rule out the histological diagnosis of PN. It is necessary to correlate clinical and histological findings together to reliably distinguish between PN and LS[13]. HLP and PN both demonstrate epidermal hyperplasia, hypergranulosis, and compact hyperkeratosis. Vertically arranged collagen fibers and an increased number of fibroblasts and capillaries in the dermis are found in both conditions. However, basal cell degeneration is limited to the tips of rete ridges, and no band-like inflammation will be seen in HLP vs. PN[14]

History and Physical

Patients with prurigo nodularis present with a characteristic firm, dome-shaped, pruritic nodules that vary in size from a few millimeters to centimeters. The nodules can be flesh-colored, erythematous, pink, and brown/black. Initially, the lesions can begin as normal skin or areas of xerosis. Due to pruritus, the patients will begin and continue to scratch the lesions until the dome-shaped nodule forms. Typically, the lesions are found symmetrically on the patient’s extensor surfaces of the arm and legs[15]. Lesions can also be found in the occipital region of the scalp. The upper back, abdomen, and sacrum also can be involved. Usually, areas that are difficult to reach such as the upper mid-back are spared. This finding is called the “butterfly sign.” The palms, soles, face, and flexural areas are usually spared. There is associated with severe pruritus that can be very distressing for the patients with prurigo nodularis. It can be sporadic or continuous and can increase with sweating, clothing irritation, or heat. Patients experience a combination of pruritic sensations including burning, stinging, and alterations in lesional temperature.[5] It has been reported that in some cases, atopic dermatitis and xerosis are found in conjunction with prurigo nodularis and may be the initiating factor. Lesions can often appear excoriated due to the pruritus involved with PN. Excoriated lesions are at increased risk of secondary infection and can appear crusted, erythematous or painful if infected. Prurigo nodularis can also be localized in the setting of an underlying local dermatosis such as venous stasis, postherpetic neuralgia, or brachioradial pruritus. [16]

Evaluation

Prurigo nodularis is a clinical diagnosis. Prurigo nodularis patients will likely have a history of chronic severe pruritus with excoriations and flesh-colored, pink nodular lesions on extensor surfaces. Dermoscopy can be a helpful tool when diagnosing PN vs. HLP. In one study, dermoscopy of HLP demonstrated pearly white areas and peripheral striations, gray-blue globules comedo-like openings, red dots and globules, brownish-black globules and yellowish structures. In PN, red dots and globules and pearly white areas with peripheral striations were observed under dermoscopy[17]. A skin biopsy may be warranted for lesions that are bleeding, have formed ulcers or are resistant to first-line therapies. If patients with prurigo nodularis and severe pruritus do not have a cause of the pruritus, causes of chronic pruritus should be evaluated. Causes of severe pruritus can include renal disease, liver disease, thyroid disease, HIV infection, malignancy or parasitic infection[18]. Evaluation of these causes includes a complete blood cell count (CBC), complete metabolic panel, thyroid studies including TSH and free T4, urinalysis, stool exam, HIV antibodies, and chest x-ray. Serum IgE levels can also be elevated in patients with PN and atopic dermatitis[19].

Treatment / Management

Management of prurigo nodularis requires a multifaceted approach. Patients need to be educated on practices to reduce scratching of lesions, assurance and diagnosing of underlying causes of pruritus and diagnosis and treatment of any psychological disorder associated with scratching and picking at skin. Treatments, both topical and systemic, are targeted at disrupting the itch-scratch cycle.

GENERAL CARE

  • Patients are encouraged to keep their nails short, wear protective clothing such as long sleeves and gloves, and to keep the nodules covered with bandages. 
  • Using gentle cleansers to bathe and applying emollients multiple times a day to keep skin moisturized should be encouraged.
  • Calamine lotions and lotions containing menthol and camphor can provide relief from the pruritus.
  • Stay in a cool comfortable environment.
  • Reduce stress. 

SPECIFIC CARE

TOPICAL AND INTRALESIONAL THERAPY

  • Although none have been examined in randomized trials, topical treatments for prurigo nodularis include class one topical corticosteroids, intralesional corticosteroids, topical calcineurin inhibitors, topical capsaicin, and topical vitamin D analogs.
  • First-line therapy is suggested to be topical corticosteroids, such as clobetasol dipropionate 0.05% ointment applied under occlusion with plastic wrap once at nighttime for at least two to four weeks.
  •  Triamcinolone acetonide in concentrations of 10 mg/mL to 20 mg/mL injected intralesionally has been shown to flatten lesions and provide relief from pruritus. [20][21][22][23][24]
  • Pimecrolimus 1% is as effective as hydrocortisone and can be implemented in a long-term regimen.[25]
  • Calcipotriol ointment shows greater efficacy as compared to betamethasone valerate 0.1%.[26]
  • The menthol in low concentration ( less than 5% ) alleviates pruritus by heightening the threshold for pruritic stimuli.[27]

ANTIHISTAMINES AND LEUKOTRINE INHIBITORS

  • High dose non sedating antihistamines for daytime followed by First-generation sedating antihistamines at bedtime. A combination of fexofenadine and montelukast gives good results.[28]Common adverse reactions to antihistamines are drowsiness, dizziness, and weakness. 

PHOTOTHERAPY/EXCIMER

  • Phototherapy with PUVA, including bath/topical PUVA, long-wavelength ultraviolet A, narrowband ultraviolet B, and monochromatic excimer light of 308 nm, have been used and shown improvement of prurigo nodularis nodules in patients.
  • Narrow Band UVB phototherapy results in significant improvement in prurigo nodularis at an average dose of 23.88= 26.00 j/cm2.[29]
  • An excimer laser is more beneficial than topical clobetasol.[30]

 ORAL IMMUNOSUPPRESSIVES

  • As with topical therapies, no randomized trials have been reported involving the use of these systemic therapies and the benefits versus risks of the drugs must be considered before beginning treatment[8]
  • Oral immunosuppressive therapy should be considered for patients with severe, recalcitrant prurigo nodularis.
  • A single-institution retrospective study demonstrated clinical improvement and a decrease in pruritus with Cyclosporine at a mean dose of 3.1 mg/kg dose.[31]
  • Methotrexate in a dose of 5-20mg/kg weekly demonstrated complete or partial remission of 2.4 months. These patients showed a mean duration of response of 19 months.[32]
  • Treatment with azathioprine and cyclophosphamide has also been reported to be successful.[33][34]
  • Oral tacrolimus therapy dramatically reduced pruritus in a patient who was previously treated with cyclosporine for prurigo nodularis.[35]
  • Combination therapy of three cycles of intravenous immunoglobulin followed by methotrexate and topical steroid was effective in prurigo nodularis associated with atopic dermatitis.[36]

NOVEL TREATMENTS

  • Thalidomide and Lenalidomide. Thalidomide is an immunomodulatory agent, which also acts as a central and peripheral depressant, and inhibits tumor necrosis factor-alpha.[36] The therapeutic effect against prurigo nodularis is thought to derive from its neurotoxic effects.[37] Lenalidomide, a more potent molecular form of thalidomide, is effective in prurigo nodularis and has a lower frequency of peripheral neuropathy.[38]
  • Both selective serotonin reuptake inhibitors and tricyclic antidepressants can also be considered for chronic pruritus. It is important for patients to also be seen in conjunction with mental health professionals. 
  • Naloxone and naltrexone exert antipruritic effect through inhibition of Mu-opioid receptors on nociceptive neurons and interneurons resulting in suppression of itch.[39]
  • NK1r antagonists, aprepitant and serlopitant, could prevent substance P mediated signaling in the pathogenesis of prurigo nodularis[40]. Significant relief of itch was achieved in prurigo nodularis patients on aprepitant monotherapy.
  • IL 31 receptor antibody, Nemolizumab, provided significant improvement in pruritus scores in patients with moderate to severe atopic dermatitis. However, its role in prurigo nodularis remains unclear.

Differential Diagnosis

  • Lichen simplex chronicus 
  • Hypertrophic lichen planus
  • Pemphigoid nodularis
  • Nodular scabies
  • Keloids
  • Dermatofibroma
  • Foreign body reactions

Treatment Planning

First Line

  • Class 1 topical steroids ( Clobetasol propionate cream, halobetasol propionate) Long term applictions can lead to skin atrophy, telangiectasia, hypopigmentation.
  • Intralesional injections of triamcinolone acetonide (40mg/ml). This may be accompanied with cryotherapy.[41][42]
  • Topical menthol solution
  • Systemic antihistamines. fexofenadine 180mg, levocetrizine 5mg during daytime and sedating antihistamines like hydroxizine25mg at night time.

Prognosis

Prurigo nodularis is a benign condition with a good prognosis. It is a chronic condition, typically preceded by an underlying cause of pruritus. However, prurigo nodularis is a distinct entity from these underlying causes and can persist despite the resolution of the predisposing condition. 

Complications

Lesions of prurigo nodularis can become secondarily infected due to scratching of the lesions. It is important to monitor for clinical signs of infection such as erythema, pain, warmth and fever. If secondary infection is suspected, it is important to begin appropriate topical or systemic antibiotic therapy to cover for skin flora. 

Pearls and Other Issues

Prurigo nodularis is a chronic skin disease that can cause a significant impact on a patients quality of life. Breaking the itch-scratch cycle requires a multifaceted approach and patients should be encouraged to continue with therapy to reduce scratching and picking at the lesions. It may be necessary to involve behavioral therapy if required. It is important to explain to patients that prurigo nodularis lesions may be chronic and very difficult to improve completely.

Enhancing Healthcare Team Outcomes

Management of prurigo nodularis requires a multidisciplinary team that includes the primary caregiver, nurse practitioner, dermatologist, and a mental health nurse. Patients need to be educated on practices to reduce scratching of lesions, assurance and diagnosing of underlying causes of pruritus and diagnosis and treatment of any psychological disorder associated with scratching and picking at skin. Treatments, both topical and systemic, are targeted at disrupting the itch-scratch cycle. Patients are encouraged to keep their nails short, wear protective clothing such as long sleeves and gloves, and to keep the nodules covered with bandages. Using gentle cleansers to bathe and applying emollients multiple times a day to keep skin moisturized should be encouraged. Calamine lotions and lotions containing menthol and camphor-like Sarna can provide relief from the pruritus. First-generation sedating antihistamines such as hydroxyzine administered at bedtime may be useful in controlling nocturnal pruritus. Both selective serotonin reuptake inhibitors and tricyclic antidepressants can also be considered for chronic pruritus. [7]

Finally, the pharmacist should educate the patient on potential adverse reactions of the medications and report back to the clinical team if there are complications.


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Prurigo Nodularis - Questions

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Prurigo Nodularis - References

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