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About the Author

Daniel Wong

Daniel Wong, MD, FRCPC

Dr. Daniel Wong is a board-certified dermatologist. He earned a Bachelor’s degree in medical sciences studying clinical biochemistry at Western University. Dr. Wong then went on to obtain his medical doctorate from Western University. He completed his 5-year dermatology residency at the University of Toronto, and currently practices at the DermCare, DerCafe and the Canadian Dermatology Centre in Toronto. His interests include skin cancer, inflammatory skin conditions such as psoriasis, and medical education.

Canadian Dermatology Today, Volume 2, Issue 4, December 2021

Prurigo Nodularis


Prurigo nodularis (PN) is a chronic, inflammatory skin disease highlighted by firm hyperkeratotic nodules and severe, unrelenting pruritus. It can affect both men and women of all ages. PN has a significant burden of disease, with a reduction in quality of life, sleep disturbances, anxiety, and depression. PN remains a challenging condition to control for many patients with currently no approved medications in Canada for its treatment. This may change however with some emerging therapeutic agents actively being investigated.1,2 


The etiology and pathogenesis of PN remain unknown but current research postulates that PN is related to both immune and neural dysregulation. The neural dysregulation is supported by increased levels of pan-neuronal marker protein gene product, and nerve growth factor in PN patients. It is also supported by increased levels of known pruritic cytokines of calcitonin-gene related peptide, substance P, and vascular endothelial growth factor (VEGF). In terms of immune dysregulation, PN is thought to be a TH2 response, showing increased infiltrates of eosinophils, T-lymphocytes, and mast cells. These cells contribute to the release of a wide range of pro-inflammatory cytokines including, but not limited to, eosinophil cationic protein (ECP), eosinophil derived neurotoxin (EDN), eosinophil protein X (EPX), major basic protein (MBP), Interleukin (IL)-4, IL-31, and prostaglandins.3 Understanding the pathophysiology can help explain the rationale for the use of certain treatments in PN. Hopefully, as researchers better understand the pathways involved in PN, more effective and targeted therapies will be developed. 


There are a variety of comorbidities that have been associated with PN. These include many of the same associations that have been linked to chronic pruritus, including atopic dermatitis, anxiety/depression, diabetes, renal disease, Hodgkin’s lymphoma, HIV, iron deficiency anemia, COPD, inflammatory bowel disease, and hepatitis. In general, more research and larger studies are required to further explore the associations between these comorbidities and PN to determine if there is a potential casual link.4

Clinical Appearance and Differential Diagnosis 

PN presents with characteristically firm, hyperkeratotic, excoriated nodules, often clustered together on at least two different extensor surfaces.5,6 (Figure 1-3) The differential diagnosis for PN includes pemphigoid nodularis, actinic prurigo, hypertrophic lichen planus, neurotic excoriations, dermatotillomania, arthropod bites, scabies, multiple keratoacanthomas and atopic dermatitis.7 

Figure 1. PN on a patient’s knees; Bolognia 4th edition

Figure 2. PN on a patient’s leg; Bolognia 4th edition

Figure 3. PN on a patient’s arm; Fitzpatrick 8th edition


Clinical Work up 

PN is primarily a clinical diagnosis of intense pruritus lasting 6 weeks or longer with the associated hyperkeratotic nodules. A skin biopsy may not always be necessary, but histology shows orthohyperkeratosis, irregular epidermal hyperplasia, hypergranulosis and an increased number of T-lymphocytes, eosinophils, fibroblasts, and capillaries.3,7 It is generally recommended that patients suspected of having PN obtain a complete blood count (CBC), a liver function test and a renal function test. Additional consideration for the screening of thyroid function, hemoglobin A1c, human immunodeficiency virus, hepatitis B and C serologies is suggested and may be warranted based on risk factors and a review of systems for the patient. In addition to this, general screenings for an underlying etiology of pruritus can also be investigated if deemed appropriate which include serum protein electrophoresis with serum immunofixation, urinalysis, a chest x-ray, iron studies and stool exam for ova and parasites. Finally, age-appropriate malignancy screening should be up to date, especially if the pruritus has been going on for less than one year.3 


Treatment of PN remains a challenging task with significant variability in the approach to disease management. All treatments are considered off-label as there are currently no approved targeted therapies for PN. Newer, emerging systemic therapies are currently being investigated in phase 3 clinical trials7,8 and may soon be available as treatment options. Current treatment modalities tend to work by targeting either the neural or immunological component of PN. In general, treatment can be divided into four categories: topicals, local/ procedural, phototherapy, and systemic options. 


The most used first-line agent for PN is high potency topical steroids. Other treatment options studied including pimecrolimus, calcitriol, topical anesthetics, and capsaicin. Table 1 provides a summary of these various options and different supporting evidence for them. In the writer’s opinion, these topical agents do provide some benefit, but are typically less effective for moderate-to-severe cases. 


Another commonly used 1st line therapy for PN is intralesional triamcinolone acetonide. This option works locally to reduce the size of nodules and decrease pruritus, but can be quite labour-intensive for severe, widespread disease. Other local and procedural options include cryotherapy and excimer laser.3,7,8 Table 1 provides more detailed summary of these options. 


Phototherapy can be an effective treatment option for some patients and is an overall a very safe modality. It can be particularly useful in many of the PN patients that have a more complex medical history where drug interactions and comorbidities can be difficult to work around. Phototherapy access and feasibility limits its use overall, and for some it still may not be sufficient at controlling their pruritus.3,7 Table 1 illustrates some further data regarding this option. 

Table 1: topicals, local and phototherapy for treatment of prurigo nodualris. b.i.d.: twice daily; prn: as needed; t.i.d.: three times daily; UVB: ultraviolet B; PUVA: psoralen + ultraviolet A.; courtesy of Daniel Wong, MD, FRCPC

Systemic Medications 

Given the severity of many cases of PN, topicals and local agents are often not sufficient for fully controlling the symptoms of PN. As a result, many different systemic agents have been studied and used historically. These include immunosuppressants such as methotrexate, cyclosporine, and mycophenolic acid; neuromodulators including gabapentinoids, amitriptyline, antidepressants and thalidomide, and newer oral agents including aprepitant and serlopitant.3,7,8 These medications deliver various levels of efficacy and are also associated with differing side effect profiles. Table 2 provides a summary of many of these agents. Antihistamines have typically been ineffective and generally are not recommended unless comorbid histamine mediated conditions are suspected.3,7 

Emerging Therapies 

There are several medications currently being investigated for treatment of PN, some of which are showing promising early results. One such agent, nemolizumab33, has recently gained “breakthrough therapy” designation by the FDA for treating PN. This process is designed to expedite the development and review of drugs that are intended to treat a serious condition where preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on clinically significant endpoint(s).34 Nemolizumab is a monoclonal antibody targeting IL-31, a proinflammatory cytokine upregulated in PN patients. Phase II studies have shown a significant reduction in pruritus scores (numerical rating scale [NRS]) in the nemolizumab treatment arm compared to the placebo group at 12 weeks. This same study also demonstrated improvements in quality of life, and a reduction in number of PN lesions.31 Currently, nemolizumab is being investigated in phase III clinical trials. 

Another newer therapy emerging as a potential effective option for PN is dupilumab. Dupilumab is a monoclonal antibody that works by inhibiting IL-4 and IL-13, which are both proinflammatory cytokines known for contributing to pruritus. Dupilumab is more well known for its treatment of atopic dermatitis but has shown in several case reports and case series to be effective at improving PN.30 Like nemolizumab, it is also undergoing phase III clinical trials. 

Other emerging treatment options being investigated for PN include oncostatin M beta receptor, opioid antagonists, and cannabinoids.7 [7]. Table 2 provides additional information about some of these newer therapies. 

Table 2: Systemic therapies for PN. PO: orally; SC: subcutaneous; SSRI: selective serotonin reuptake inhibitors; GI: gastrointestinal; MSK: musculoskeletal; CNS: central nervous system; RCT: randomized control study; courtesy of Daniel Wong, MD, FRCPC


PN is chronic inflammatory skin disease that is often clinically challenging. Although strides have been made in recent years with understanding this condition and with the development of newer therapeutic agents, further research into the pathophysiology and targeted treatment modalities are still needed to better understand PN. 


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10. Siepmann D, Lotts T, Blome C, et al. 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. 2014;227(4):353-360. 

11. Ständer S, Luger T, Metze D. Treatment of prurigo nodularis with topical capsaicin. J Am Acad Dermatol. 2001;44(3):471-478. 

12. Huang AH, Canner JK, Kang S, et al. Analysis of real-world treatment patterns in patients with prurigo nodularis. J Am Acad Dermatol. 2020 Jan;82(1):34-36. 

13. Stoll DM, Fields JP, King LE. Treatment of Prurigo Nodularis: Use of cryosurgery and intralesional steroids plus lidocaine. J Derm Surg Onc. 1983;9(11): 922-924. 

14. Wong SS, Goh CL. Double-blind, right/ left comparison of calcipotriol ointment and betamethasone ointment in the treatment of prurigo nodularis. Arch Dermatol. 2000;136:807- 808. 

15. Hann SK, Cho MY, Park YK. UV treatment of generalized prurigo nodularis. Int J Dermatol. 1990 Jul-Aug;29(6):436-7. 

16. Rombold, S., Lobisch, K., Katzer, K., Grazziotin, T. C., Ring, J., & Eberlein, B. Efficacy of UVA1 phototherapy in 230 patients with various skin diseases. Photodermatology, Photoimmunology & Photomedicine. 2008;24(1):19–23. 

17. Brenninkmeijer EEA, 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;163: 823-831. 

18. Andersen TP, Fogh K. Thalidomide in 42 patients with prurigo nodularis hyde. Dermatology. 2011;223:107-112. 

19. Sharma D, Kwatra SG. Thalidomide for the treatment of chronic refractory pruritus. J Am Acad Dermatol. 2016;74:363-369 

20. Spring P, Gschwind I, Gilliet M. Prurigo nodularis: retrospective study of 13 cases managed with methotrexate. Clin Exp Dermatol. 2014;39:468-473. 

21. Klejtman T, Beylot-Barry M, Joly P, et al. Treatment of prurigo with methotrexate: a multicentre retrospective study of 39 cases. J Eur Acad Dermatol Venereol. 2018;32:437-440. 

22. Siepmann D, Luger TA, Stander S. Antipruritic effect of cyclosporine microemulsion in prurigo nodularis: results of a case series. J Dtsch Dermatol Ges. 2008;6:941-946. 

23. Wiznia LE, Callahan SW, Cohen DE, Orlow SJ. Rapid improvement of prurigo nodularis with cyclosporine treatment. J Am Acad Dermatol. 2018;78:1209-1211. 

24. Mazza M, Guerriero G, Marano G, Janiri L, Bria P, Mazza S. Treatment of prurigo nodularis with pregabalin. J Clin Pharm Ther. 2013;38:16-18. 

25. Gencoglan G, Inanir I, Gunduz K. Treatment of prurigo nodularis and lichen simplex chronicus with gabapentin. Derm Therap. 2010;23(2):194-198. 

26. Zalaudek I, Petrillo G, Baldassarre MA, et al. Amitriptyline as therapeutic and not symptomatic approach in the treatment of prurigo nodularis: a pilot study. G Ital Dermatol Venereol. 2006;141:433-437. 

27. Stander S, Bockenholt B, Schurmeyer- Horst F, et al. Treatment of chronic pruritus with the selective serotonin re-uptake inhibitors paroxetine and fluvoxamine: results of an open-labelled, two-arm proof-of-concept study. Acta Derm Venereol. 2009;89:45-51. 

28. Jaller J, Yosipovitch G. Successful treatment of epidermal nevus-associated pruritus with topical ketamineeamitriptylinee lidocaine. Acta Derm Venereol. 2018;98:121-122 

29. Stander S, Kwon P, Luger T. A randomized, double-blind, placebo-controlled, study of the neurokinin-1 receptor (nk1-r) antagonist serlopitant in subjects with prurigo nodularis (PN). Paper presented at: American Academy of Dermatology Annual Meeting. March 3-7, 2017; 

30. Maredia H, Kwatra SG. Emerging novel therapeutic agents for the treatment of patients with prurigo nodularis. J Dermatolog Treat. 2020 Jan; 3;1-4. 

31. Stander S, Yosipovitch G, Legat FJ, Lacour JP, Paul C, Narbutt J, Bieber T, Misery L, Wollenberg A, Reich A, Ahmad F, Piketty C. Trial of Nemolizumab in Moderate-to-Severe Prurigo Nodularis. N Engl J Med. 2020 Feb;382(8):706-716. 

32. Stander S, Reinhardt HW, Luger TA. Topical cannabinoid agonists: an effective new possibility for treating chronic pruritus. Der Hautarzt. 2006;57:801–807 

33. Park B. Nemolizumab Gets Breakthrough Therapy Status for Prurigo Nodularis empr.com2019 [updated December 9; cited 2021, Aug 25]. Available from: nemolizumab-gets-breakthrough-therapy-status-forprurigo-nodularis/