Continuing Education Activity

Prurigo nodularis (PN) is a chronic skin disorder characterized by multiple, firm, flesh-to-pink colored papules, plaques, and nodules predominantly found on the extensor surfaces of the extremities. These lesions are intensely pruritic and manifest across diverse age groups. PN often coexists with other cutaneous hypersensitivity disorders, such as atopic dermatitis or chronic pruritus, making its diagnosis primarily clinical yet necessitating differentiation from similar conditions like lichen simplex chronicus or hypertrophic lichen planus. Dermoscopy and histopathology serve as crucial tools for diagnostic confirmation in challenging cases.

Management of PN encompasses a multifaceted approach involving potent antipruritics, immunomodulators, and neuromodulators tailored to patients' specific needs. Long-term therapy is often necessary as PN tends to be refractory to conventional treatments, emphasizing the importance of patient education, counseling, and compliance. This activity reviews the evaluation and comprehensive management strategies for PN, highlighting the role of the interprofessional team in caring for patients with this debilitating skin condition, considering both its physical and psychological ramifications.

Objectives:

• Identify the etiology of prurigo nodularis (PN), including its association with diverse cutaneous hypersensitivity disorders like atopic dermatitis, chronic pruritus, and other potential underlying conditions.
• Evaluate PN lesions through history, examination, and lab testing to confirm diagnosis and differentiate them from other dermatological conditions with similar clinical presentations. 
• Determine the treatment plan and management options available for PN based on individual patient needs and the chronic, refractory nature of the condition. 
• Collaborate with the interprofessional team to optimize management strategies for improved patient outcomes.

Introduction

Prurigo nodularis (PN) 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 very pruritic, and the condition may occur in any age group. It is commonly associated with another disorder of cutaneous hypersensitivity, such as atopic dermatitis or chronic pruritus of diverse origins. The diagnosis is mainly clinical, although certain conditions may simulate it clinically, warranting differentiation. The condition is associated with significant physical and psychological morbidity and is often refractory to treatments. A wide range of general measures, pharmacological approaches, and psychological therapies may be needed in a patient with advanced PN.[1][2][3][4]

Etiology

The exact etiology of PN remains poorly understood. Although the role of the unimpeded itch-scratch cycle is uncontested, the exact sequence of events leading to the final clinical picture remains debated. PN is accompanied by long-standing pruritus and is thought to develop as a reaction to repeated scratching in patients with chronic prurigo of various etiologies, including dermatological, systemic, infectious, and neuropsychiatric.[5][6] Anecdotal data suggest a causative role or association of infectious agents such as hepatitis C, Helicobacter pylori, Strongyloides stercoralis, mycobacteria, and HIV.[7][8] 

An increase in the number of sensory structures of the epidermis (Merkel cells) and dermis (papillary dermal nerves) is encountered in PN lesions.[9] This neural alteration is typical of PN and not seen in lichen simplex chronicus or neurodermatitis. The density of mast cells and neutrophils is also increased in PN, although there seems to be no increase in their degranulation products. In contrast, although the number of eosinophils remains maintained, their products, such as the major basic protein and eosinophil-derived neurotoxin, show higher than normal levels.

The pruritus in PN seems to be a result of cutaneous neurogenic inflammation mediated by various neuropeptides, especially substance P, calcitonin gene–related peptide (CGRP),[10] and vanilloid receptor subtype 1 (VR-1). The latter binds to capsaicin, rendering it a potential therapeutic topical agent. Individuals with PN also show elevated levels of interleukin 31 (IL-31), a T-cell–derived highly prurigogenic cytokine.[11]

Epidemiology

The exact incidence of PN is unknown. A majority of patients with PN present between the ages of 51 and 65 years, although several cases in other age groups have also been described.[5][12] The disease afflicts both genders; however, it seems to be more frequent and more intense in females.[13] Multiple studies have shown that individuals with an atopic predisposition have an earlier age of onset.[5][14][15] Ethnicity and genetic predisposition seem to play a role since African-Americans are 3 to 4 times more likely to have PN than white patients.[12] Other conditions that have been reported to induce PN include internal malignancy, renal failure, and psychiatric conditions. In HIV-positive patients, PN has been reported to be predictive of advanced immunosuppression.[16] 

Pathophysiology

The pathophysiology of PN has been controversial. Chronic or recurrent mechanical trauma or vigorous frictional assault to the skin induces epidermal hyperplasia with resultant thickening of the skin. Repetitive mechanical rubbing and scratching of the skin result in the formation of plaques and nodules (often with lichenification) and also give rise to dyschromic changes (typically hyperpigmentation). The itching of PN is typically episodic, severe, and uncontrollable; it tends to occur at discrete points that eventually transform into hyperpigmented nodular plaques with excoriations, crusting, and sometimes secondary bacterial infection.

Immunohistochemical studies have shown increased dermal nerve fibers in the papillary dermis of patients with PN. It has been postulated that the thin, unmyelinated epidermal nerves are the transmitters of severe prurigo. Nerve growth factor (NGF) and its receptor, tyrosine receptor kinase A (TrkA), are overexpressed in PN lesions; both may also be associated with the increased release and accumulation of neuropeptides, such as substance P and calcitonin gene–related peptides.[17] Interestingly, skin biopsies taken from lesions of PN tend to show significantly decreased intraepidermal—not dermal—nerve fiber density. Although this finding has raised doubt about some subclinical small nerve fiber neuropathy contributing to the pathophysiology of PN, recent studies have suggested that the reduction may be secondary to chronic scratching. This suggestion was confirmed by observing restoration of the intraepidermal nerve fiber density on complete healing of lesions.[18]

The role of helper T cytokines (T helper 1 [Th1] and T helper 2 [Th2]) has also been studied in the pathogenesis of PN using the signal transducers and activators of transcription (STAT) 1, 3, and 6. In all but 3 cases, the entire epidermis was stained with anti–phosphorylated STAT (pSTAT) 6, a marker for the Th2 cytokines IL-4, IL-5, and IL-13. These findings suggest that Th2 cytokines play a principal role in the pathogenesis of PN.[19] 

Histopathology

PN lesions 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.

Histology can be important in differentiating PN from lichen simplex (LS) and hypertrophic lichen planus (HLP). LS lesions are less likely to have pseudoepitheliomatous hyperplasia or nerve fiber thickening; however, these findings do not rule out the histological diagnosis of PN. To reliably distinguish between PN and LS, it is necessary to correlate clinical and histological findings.[20] 

HLP and PN both demonstrate epidermal hyperplasia, hypergranulosis, and compact hyperkeratosis. Vertically arranged collagen fibers and increased 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 versus PN[21]

History and Physical

Patients with PN present with characteristic firm, dome-shaped, pruritic nodules that vary from a few millimeters to a few centimeters. The nodules can be flesh-colored, erythematous, pink, and brown/black. The lesions can begin as normal skin or areas of xerosis; patients will scratch them due to pruritus until the dome-shaped nodule forms. Typically, the lesions are found symmetrically on the extensor surfaces of the arm and legs.[22] Lesions can also be found in the occipital region of the scalp. The upper back, abdomen, and sacrum also can be involved.

Areas of the body that are difficult to reach, such as the upper mid-back, are usually spared from PN lesions, a finding called the “butterfly sign.” The palms, soles, face, and flexural areas are also usually spared. PN lesions cause severe pruritus, which can be very distressing for patients. It can be sporadic or continuous and can increase with sweating, clothing irritation, or heat. In addition to pruritic sensations, patients can experience 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 PN 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. PN can also be localized in cases of underlying local dermatosis such as venous stasis, postherpetic neuralgia, or brachioradial pruritus.[23]

Evaluation

PN is a clinical diagnosis. Patients with PN 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 versus 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.[24] A skin biopsy may be warranted for lesions that are bleeding, have formed ulcers, or are resistant to first-line therapies.

In patients with PN and severe pruritus, underlying causes of severe pruritus should be evaluated, including renal disease, liver disease, thyroid disease, HIV infection, malignancy, or parasitic infection.[25] Evaluation of these causes includes a complete blood cell count, complete metabolic panel, thyroid studies including thyroid-stimulating hormone and free thyroxine (T4), urinalysis, stool exam, HIV antibodies, and chest X-ray. Serum immunoglobulin E levels can also be elevated in patients with PN and atopic dermatitis.[26]

Treatment / Management

Management of PN requires a multifaceted approach. Patients need to be educated on practices to reduce scratching of lesions. Further, any psychological disorder associated with scratching and picking at skin should be diagnosed and treated. Any underlying causes of pruritus should also be diagnosed. Treatments for PN, both topical and systemic, are targeted at disrupting the itch-scratch cycle.

General Care

Patients with PN should be advised to: 

• Keep their nails short, wear protective clothing (ie, long sleeves and gloves), and keep the nodules covered with bandages. 
• Bathe with gentle cleansers and apply emollients throughout day to keep skin moisturized.
• Use calamine lotions and lotions containing menthol and camphor to provide itch relief.
• 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 PN include class I topical corticosteroids, intralesional corticosteroids, topical calcineurin inhibitors, topical capsaicin, and topical vitamin D analogs.
• The suggested first-line therapy consists of topical corticosteroids, such as clobetasol dipropionate 0.05% ointment, applied under occlusion with plastic wrap once at nighttime for at least 2 to 4 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.[27][28][29][30][31]
• Pimecrolimus 1% is as effective as hydrocortisone and can be implemented in a long-term regimen.[32]
• Calcipotriol ointment shows greater efficacy than betamethasone valerate 0.1%.[33]
• Low concentrations of menthol (<5%) alleviate pruritus by heightening the threshold for pruritic stimuli.[34]

Antihistamines and Leukotriene Inhibitors 

• High-dose nonsedating antihistamines can be used during the day, followed by first-generation sedating antihistamines at bedtime; a combination of fexofenadine and montelukast gives good results.[35] 
• Common adverse reactions to antihistamines are drowsiness, dizziness, and weakness. 

Phototherapy and Excimer Laser

• Phototherapy with psoralen–ultraviolet-A (PUVA), including bath and topical PUVA, long-wavelength UVA, narrowband UVB, and monochromatic excimer light of 308 nm, have been used and shown improvement of PN nodules.
• Narrow band UVB phototherapy significantly improves PN at an average dose of 23.88-26.00 j/cm².[36]
• An excimer laser is more beneficial than topical clobetasol.[37]

 Oral Immunosuppressants 

• As with topical therapies, no randomized trials have been reported involving these systemic therapies, and the benefits versus risks of the drugs must be considered before beginning treatment.[13]
• Oral immunosuppressive therapy should be considered for patients with severe, recalcitrant PN.
• A single-institution retrospective study demonstrated clinical improvement and decreased pruritus with cyclosporine at a mean dose of 3.1 mg/kg.[38]
• Methotrexate dosed at 5 to 20 mg/kg weekly demonstrated complete or partial remission of 2.4 months. These patients showed a mean duration of response of 19 months.[39]
• Treatment with azathioprine and cyclophosphamide has also been reported to be successful.[40][41]
• Oral tacrolimus therapy dramatically reduced pruritus in a patient previously treated with cyclosporine.[42]
• Combination therapy of 3 cycles of intravenous immunoglobulin followed by methotrexate and topical steroids was effective in treating PN associated with atopic dermatitis.[43]

Novel Treatments 

• Thalidomide is an immunomodulatory agent which also acts as a central and peripheral depressant and inhibits tumor necrosis factor-alpha.[43] The therapeutic effect against PN is thought to derive from its neurotoxic effects.[44]
• Lenalidomide, a more potent molecular form of thalidomide, is effective in PN and has a lower frequency of peripheral neuropathy.[45]
• Both selective serotonin reuptake inhibitors and tricyclic antidepressants can also be considered for chronic pruritus. It is also important for patients alsbe seen in conjunction with mental health professionals. 
• Naloxone and naltrexone exert antipruritic effects by inhibiting Mu-opioid receptors on nociceptive neurons and interneurons, resulting in suppression of itch.[46]
• Neurokinin-1 receptor (NK1r) antagonists, aprepitant and serlopitant, could prevent substance P–mediated signaling in the pathogenesis of PN.[47] Significant relief of itch was achieved in PN patients on aprepitant monotherapy.
• IL 31 receptor antibody, nemolizumab, significantly improved pruritus scores in patients with moderate to severe atopic dermatitis; however, its role in PN remains unclear.

Differential Diagnosis

Due to similar morphologies, PN is often confused with and must be clinically separated from:

• LS chronicus 
• HLP
• Pemphigoid nodularis
• Nodular scabies
• Keloids
• Dermatofibroma
• Foreign body reactions

Treatment Planning

Treatment of PN should be tailored to a patient's age, comorbidities, severity of prurigo, quality of life, and expected side effects.

First-line Therapy

• Class I topical steroids: Clobetasol propionate 0.05% and halobetasol propionate 0.05%); long-term applications can lead to adverse effects like skin atrophy, folliculitis, miliaria, delayed wound healing, and tachyphylaxis.
• Intralesional injections: Using triamcinolone acetonide (40 mg/ml); may be accompanied by cryotherapy[48][49]
• Topical menthol solution: In a concentration of less than 5%.
• Systemic antihistamines: Fexofenadine 180 mg, levocetirizine 5 mg, or desloratadine 5 mg during the day, and sedating antihistamines like hydroxyzine 25 mg at night time; first-generation antihistamines cause side effects like sedation, hyperexcitability, impaired cognitive function, dry mouth, constipation, dysuria, tachycardia, and arrhythmias.

Second-line Therapy

• Phototherapy: PUVA, long-wavelength UVA, Narrowband UVB, monochromatic excimer light of 308nm
• Systemic immunosuppressives: Cyclosporine 3 mg/kg daily; adverse effects include nephrotoxicity, hypertension, hyperlipidemia, hyperkalemia, and hyperuricemia. Methotrexate 5-20 mg/week; common adverse effects are nausea, gastrointestinal symptoms, and transaminitis.
• Thalidomide: Dosed at 300-400 mg daily yields a good response within 3 months, followed by tapering the dose to 50 mg daily; however, complete cessation of the drug leads to recurrences. Adverse effects are teratogenicity and peripheral neuropathy.
• Lenalidomide: Dosed at 5-10 mg daily; less neurotoxic than thalidomide.
• Opioid receptor antagonists: Naltrexone 50 mg daily; adverse effects are restricted to the first 2 weeks of treatment and include nausea, fatigue, dizziness, heartburn, and diarrhea. 

Prognosis

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

Complications

PN lesions can become secondarily infected due to scratching of the lesions, leading to ulceration, abscess formation, and cellulitis. 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. 

Deterrence and Patient Education

The deterrents in PN treatment are the severe intensity of the itch, which can lead to psychological distress, the chronic nature of the condition, the long duration of the therapy, and the potential side effects of the medication.

Discussion with the patient should include the advantages and disadvantages of the therapy, side effects, and possible use of off-label medications. Patient education can thus promote treatment adherence. The potential length of therapy should also be discussed as PN is difficult to treat, and the patient may become frustrated with the lack of improvement.

Pearls and Other Issues

PN is a chronic skin disease that can significantly impact a patient's 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. It is important to explain to patients that PN lesions may be chronic and difficult to completely improve.

Enhancing Healthcare Team Outcomes

Management of PN requires an interprofessional team that includes the primary caregiver, nurse practitioner, dermatologist, and 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.

Topical and systemic treatments 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 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 relieve 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.[12]

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

Review Questions

• Access free multiple choice questions on this topic.
• Click here for a simplified version.
• Comment on this article.

References

1.

Harbaoui S, Litaiem N. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Feb 13, 2023. Acquired Perforating Dermatosis. [PubMed: 30969537]

2.

Larson VA, Tang O, Stander S, Miller LS, Kang S, Kwatra SG. Association between prurigo nodularis and malignancy in middle-aged adults. J Am Acad Dermatol. 2019 Nov;81(5):1198-1201. [PMC free article: PMC7377235] [PubMed: 30954580]

3.

Ständer S, Kwon P, Hirman J, Perlman AJ, Weisshaar E, Metz M, Luger TA., TCP-102 Study Group. Serlopitant reduced pruritus in patients with prurigo nodularis in a phase 2, randomized, placebo-controlled trial. J Am Acad Dermatol. 2019 May;80(5):1395-1402. [PubMed: 30894279]

4.

Kowalski EH, Kneiber D, Valdebran M, Patel U, Amber KT. Treatment-resistant prurigo nodularis: challenges and solutions. Clin Cosmet Investig Dermatol. 2019;12:163-172. [PMC free article: PMC6400231] [PubMed: 30881076]

5.

Iking A, Grundmann S, Chatzigeorgakidis E, Phan NQ, Klein D, Ständer S. Prurigo as a symptom of atopic and non-atopic diseases: aetiological survey in a consecutive cohort of 108 patients. J Eur Acad Dermatol Venereol. 2013 May;27(5):550-7. [PubMed: 22364653]

6.

Rowland Payne CM, Wilkinson JD, McKee PH, Jurecka W, Black MM. Nodular prurigo--a clinicopathological study of 46 patients. Br J Dermatol. 1985 Oct;113(4):431-9. [PubMed: 4063179]

7.

Mattila JO, Vornanen M, Vaara J, Katila ML. Mycobacteria in prurigo nodularis: the cause or a consequence? J Am Acad Dermatol. 1996 Feb;34(2 Pt 1):224-8. [PubMed: 8642086]

8.

Jacob CI, Patten SF. Strongyloides stercoralis infection presenting as generalized prurigo nodularis and lichen simplex chronicus. J Am Acad Dermatol. 1999 Aug;41(2 Pt 2):357-61. [PubMed: 10426933]

9.

Nahass GT, Penneys NS. Merkel cells and prurigo nodularis. J Am Acad Dermatol. 1994 Jul;31(1):86-8. [PubMed: 7517411]

10.

Vaalasti A, Suomalainen H, Rechardt L. Calcitonin gene-related peptide immunoreactivity in prurigo nodularis: a comparative study with neurodermatitis circumscripta. Br J Dermatol. 1989 May;120(5):619-23. [PubMed: 2474315]

11.

Sonkoly E, Muller A, Lauerma AI, Pivarcsi A, Soto H, Kemeny L, Alenius H, Dieu-Nosjean MC, Meller S, Rieker J, Steinhoff M, Hoffmann TK, Ruzicka T, Zlotnik A, Homey B. IL-31: a new link between T cells and pruritus in atopic skin inflammation. J Allergy Clin Immunol. 2006 Feb;117(2):411-7. [PubMed: 16461142]

12.

Boozalis E, Tang O, Patel S, Semenov YR, Pereira MP, Stander S, Kang S, Kwatra SG. Ethnic differences and comorbidities of 909 prurigo nodularis patients. J Am Acad Dermatol. 2018 Oct;79(4):714-719.e3. [PMC free article: PMC6518410] [PubMed: 29733939]

13.

Fostini AC, Girolomoni G, Tessari G. Prurigo nodularis: an update on etiopathogenesis and therapy. J Dermatolog Treat. 2013 Dec;24(6):458-62. [PubMed: 23767411]

14.

Tanaka M, Aiba S, Matsumura N, Aoyama H, Tagami H. Prurigo nodularis consists of two distinct forms: early-onset atopic and late-onset non-atopic. Dermatology. 1995;190(4):269-76. [PubMed: 7655104]

15.

Tan WS, Tey HL. Extensive prurigo nodularis: characterization and etiology. Dermatology. 2014;228(3):276-80. [PubMed: 24662043]

16.

Magand F, Nacher M, Cazorla C, Cambazard F, Marie DS, Couppié P. Predictive values of prurigo nodularis and herpes zoster for HIV infection and immunosuppression requiring HAART in French Guiana. Trans R Soc Trop Med Hyg. 2011 Jul;105(7):401-4. [PubMed: 21621233]

17.

Lee MR, Shumack S. Prurigo nodularis: a review. Australas J Dermatol. 2005 Nov;46(4):211-18; quiz 219-20. [PubMed: 16197418]

18.

Pereira MP, Mühl S, Pogatzki-Zahn EM, Agelopoulos K, Ständer S. Intraepidermal Nerve Fiber Density: Diagnostic and Therapeutic Relevance in the Management of Chronic Pruritus: a Review. Dermatol Ther (Heidelb). 2016 Dec;6(4):509-517. [PMC free article: PMC5120635] [PubMed: 27730494]

19.

Fukushi S, Yamasaki K, Aiba S. Nuclear localization of activated STAT6 and STAT3 in epidermis of prurigo nodularis. Br J Dermatol. 2011 Nov;165(5):990-6. [PubMed: 21711341]

20.

Weigelt N, Metze D, Ständer S. Prurigo nodularis: systematic analysis of 58 histological criteria in 136 patients. J Cutan Pathol. 2010 May;37(5):578-86. [PubMed: 20002240]

21.

Ankad BS, Beergouder SL. Hypertrophic lichen planus versus prurigo nodularis: a dermoscopic perspective. Dermatol Pract Concept. 2016 Apr;6(2):9-15. [PMC free article: PMC4866621] [PubMed: 27222766]

22.

Vaidya DC, Schwartz RA. Prurigo nodularis: a benign dermatosis derived from a persistent pruritus. Acta Dermatovenerol Croat. 2008;16(1):38-44. [PubMed: 18358109]

23.

Pereira MP, Lüling H, Dieckhöfer A, Steinke S, Zeidler C, Ständer S. Brachioradial Pruritus and Notalgia Paraesthetica: A Comparative Observational Study of Clinical Presentation and Morphological Pathologies. Acta Derm Venereol. 2018 Jan 12;98(1):82-88. [PubMed: 28902951]

24.

Nair PA, Patel T. Dermatoscopic Features of Prurigo Nodularis. Indian Dermatol Online J. 2019 Mar-Apr;10(2):187-189. [PMC free article: PMC6434741] [PubMed: 30984602]

25.

Nowak DA, Yeung J. Diagnosis and treatment of pruritus. Can Fam Physician. 2017 Dec;63(12):918-924. [PMC free article: PMC5729138] [PubMed: 29237630]

26.

Przybilla B, Ring J, Völk M. [Total IgE levels in the serum in dermatologic diseases]. Hautarzt. 1986 Feb;37(2):77-82. [PubMed: 3957665]

27.

Katayama C, Hayashida Y, Sugiyama S, Shiohara T, Aoyama Y. Corticosteroid-resistant prurigo nodularis: a rare syringotropic variant associated with hypohidrosis. Eur J Dermatol. 2019 Apr 01;29(2):212-213. [PubMed: 30827950]

28.

Legat FJ. The Antipruritic Effect of Phototherapy. Front Med (Lausanne). 2018;5:333. [PMC free article: PMC6287194] [PubMed: 30560129]

29.

Gupta MA, Pur DR, Vujcic B, Gupta AK. Use of antiepileptic mood stabilizers in dermatology. Clin Dermatol. 2018 Nov-Dec;36(6):756-764. [PubMed: 30446200]

30.

Beck KM, Yang EJ, Sekhon S, Bhutani T, Liao W. Dupilumab Treatment for Generalized Prurigo Nodularis. JAMA Dermatol. 2019 Jan 01;155(1):118-120. [PubMed: 30427994]

31.

Qureshi AA, Abate LE, Yosipovitch G, Friedman AJ. A systematic review of evidence-based treatments for prurigo nodularis. J Am Acad Dermatol. 2019 Mar;80(3):756-764. [PubMed: 30261199]

32.

Siepmann D, Lotts T, Blome C, Braeutigam M, Phan NQ, Butterfass-Bahloul T, Augustin M, Luger TA, Ständer S. Evaluation of the antipruritic effects of topical pimecrolimus in non-atopic prurigo nodularis: results of a randomized, hydrocortisone-controlled, double-blind phase II trial. Dermatology. 2013;227(4):353-60. [PubMed: 24281309]

33.

Wong SS, Goh CL. Double-blind, right/left comparison of calcipotriol ointment and betamethasone ointment in the treatment of Prurigo nodularis. Arch Dermatol. 2000 Jun;136(6):807-8. [PubMed: 10871962]

34.

Patel T, Ishiuji Y, Yosipovitch G. Menthol: a refreshing look at this ancient compound. J Am Acad Dermatol. 2007 Nov;57(5):873-8. [PubMed: 17498839]

35.

Shintani T, Ohata C, Koga H, Ohyama B, Hamada T, Nakama T, Furumura M, Tsuruta D, Ishii N, Hashimoto T. Combination therapy of fexofenadine and montelukast is effective in prurigo nodularis and pemphigoid nodularis. Dermatol Ther. 2014 May-Jun;27(3):135-9. [PubMed: 24102897]

36.

Hammes S, Hermann J, Roos S, Ockenfels HM. UVB 308-nm excimer light and bath PUVA: combination therapy is very effective in the treatment of prurigo nodularis. J Eur Acad Dermatol Venereol. 2011 Jul;25(7):799-803. [PubMed: 20946583]

37.

Brenninkmeijer EE, Spuls PI, Lindeboom R, van der Wal AC, Bos JD, Wolkerstorfer A. Excimer laser vs. clobetasol propionate 0·05% ointment in prurigo form of atopic dermatitis: a randomized controlled trial, a pilot. Br J Dermatol. 2010 Oct;163(4):823-31. [PubMed: 20491772]

38.

Wiznia LE, Callahan SW, Cohen DE, Orlow SJ. Rapid improvement of prurigo nodularis with cyclosporine treatment. J Am Acad Dermatol. 2018 Jun;78(6):1209-1211. [PubMed: 29438756]

39.

Klejtman T, Beylot-Barry M, Joly P, Richard MA, Debarbieux S, Misery L, Wolkenstein P, Chosidow O, Ingen-Housz-Oro S. Treatment of prurigo with methotrexate: a multicentre retrospective study of 39 cases. J Eur Acad Dermatol Venereol. 2018 Mar;32(3):437-440. [PubMed: 29055135]

40.

Lear JT, English JS, Smith AG. Nodular prurigo responsive to azathioprine. Br J Dermatol. 1996 Jun;134(6):1151. [PubMed: 8763446]

41.

Gupta R. Treatment of prurigo nodularis with dexamethasone-cyclophosphamide pulse therapy. Indian J Dermatol Venereol Leprol. 2016 Mar-Apr;82(2):239. [PubMed: 26924412]

42.

Halvorsen JA, Aasebø W. Oral tacrolimus treatment of pruritus in prurigo nodularis. Acta Derm Venereol. 2015 Sep;95(7):866-7. [PubMed: 25804254]

43.

Feldmeyer L, Werner S, Kamarashev J, French LE, Hofbauer GF. Atopic prurigo nodularis responds to intravenous immunoglobulins. Br J Dermatol. 2012 Feb;166(2):461-2. [PubMed: 21910702]

44.

Chen M, Doherty SD, Hsu S. Innovative uses of thalidomide. Dermatol Clin. 2010 Jul;28(3):577-86. [PubMed: 20510766]

45.

Kanavy H, Bahner J, Korman NJ. Treatment of refractory prurigo nodularis with lenalidomide. Arch Dermatol. 2012 Jul;148(7):794-6. [PubMed: 22801610]

46.

Phan NQ, Lotts T, Antal A, Bernhard JD, Ständer S. Systemic kappa opioid receptor agonists in the treatment of chronic pruritus: a literature review. Acta Derm Venereol. 2012 Sep;92(5):555-60. [PubMed: 22504709]

47.

Haas S, Capellino S, Phan NQ, Böhm M, Luger TA, Straub RH, Ständer S. Low density of sympathetic nerve fibers relative to substance P-positive nerve fibers in lesional skin of chronic pruritus and prurigo nodularis. J Dermatol Sci. 2010 Jun;58(3):193-7. [PubMed: 20417061]

48.

Waldinger TP, Wong RC, Taylor WB, Voorhees JJ. Cryotherapy improves prurigo nodularis. Arch Dermatol. 1984 Dec;120(12):1598-600. [PubMed: 6508332]

49.

Stoll DM, Fields JP, King LE. Treatment of prurigo nodularis: use of cryosurgery and intralesional steroids plus lidocaine. J Dermatol Surg Oncol. 1983 Nov;9(11):922-4. [PubMed: 6630706]

Disclosure: Tessa Mullins declares no relevant financial relationships with ineligible companies.

Disclosure: Poonam Sharma declares no relevant financial relationships with ineligible companies.

Disclosure: Christopher Riley declares no relevant financial relationships with ineligible companies.

Disclosure: Hasnain Syed declares no relevant financial relationships with ineligible companies.

Disclosure: Sidharth Sonthalia declares no relevant financial relationships with ineligible companies.