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.
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. 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 
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. It seems to be more frequent and more intense in females. It is seen as one of the clinical presentations of adult-onset atopic dermatitis.In HIV positive patients, prurigo nodularis s predictive of advanced immunosuppression.
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. 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.
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. 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
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. 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. 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. 
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. 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. 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.
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.
TOPICAL AND INTRALESIONAL THERAPY
ANTIHISTAMINES AND LEUKOTRINE INHIBITORS
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.
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.
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.
Management of prurigo nodularis requires an interprofessional 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. 
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.
|||Harbaoui S,Litaiem N, Acquired Perforating Dermatosis 2019 Jan; [PubMed PMID: 30969537]|
|||Larson VA,Tang O,Stander S,Miller LS,Kang S,Kwatra SG, Association between prurigo nodularis and malignancy in middle-aged adults. Journal of the American Academy of Dermatology. 2019 Apr 4; [PubMed PMID: 30954580]|
|||Ständer S,Kwon P,Hirman J,Perlman AJ,Weisshaar E,Metz M,Luger TA, Serlopitant reduced pruritus in patients with prurigo nodularis in a phase 2, randomized, placebo-controlled trial. Journal of the American Academy of Dermatology. 2019 Mar 17; [PubMed PMID: 30894279]|
|||Kowalski EH,Kneiber D,Valdebran M,Patel U,Amber KT, Treatment-resistant prurigo nodularis: challenges and solutions. Clinical, cosmetic and investigational dermatology. 2019; [PubMed PMID: 30881076]|
|||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. Journal of the European Academy of Dermatology and Venereology : JEADV. 2013 May [PubMed PMID: 22364653]|
|||Rowland Payne CM,Wilkinson JD,McKee PH,Jurecka W,Black MM, Nodular prurigo--a clinicopathological study of 46 patients. The British journal of dermatology. 1985 Oct [PubMed PMID: 4063179]|
|||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. Journal of the American Academy of Dermatology. 2018 Oct; [PubMed PMID: 29733939]|
|||Fostini AC,Girolomoni G,Tessari G, Prurigo nodularis: an update on etiopathogenesis and therapy. The Journal of dermatological treatment. 2013 Dec [PubMed PMID: 23767411]|
|||Silvestre Salvador JF,Romero-Pérez D,Encabo-Durán B, Atopic Dermatitis in Adults: A Diagnostic Challenge. Journal of investigational allergology [PubMed PMID: 28071589]|
|||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. Transactions of the Royal Society of Tropical Medicine and Hygiene. 2011 Jul [PubMed PMID: 21621233]|
|||Lee MR,Shumack S, Prurigo nodularis: a review. The Australasian journal of dermatology. 2005 Nov [PubMed PMID: 16197418]|
|||Fukushi S,Yamasaki K,Aiba S, Nuclear localization of activated STAT6 and STAT3 in epidermis of prurigo nodularis. The British journal of dermatology. 2011 Nov [PubMed PMID: 21711341]|
|||Weigelt N,Metze D,Ständer S, Prurigo nodularis: systematic analysis of 58 histological criteria in 136 patients. Journal of cutaneous pathology. 2010 May [PubMed PMID: 20002240]|
|||Ankad BS,Beergouder SL, Hypertrophic lichen planus versus prurigo nodularis: a dermoscopic perspective. Dermatology practical & conceptual. 2016 Apr [PubMed PMID: 27222766]|
|||Vaidya DC,Schwartz RA, Prurigo nodularis: a benign dermatosis derived from a persistent pruritus. Acta dermatovenerologica Croatica : ADC. 2008 [PubMed PMID: 18358109]|
|||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 dermato-venereologica. 2018 Jan 12 [PubMed PMID: 28902951]|
|||Nair PA,Patel T, Dermatoscopic Features of Prurigo Nodularis. Indian dermatology online journal. 2019 Mar-Apr [PubMed PMID: 30984602]|
|||Nowak DA,Yeung J, Diagnosis and treatment of pruritus. Canadian family physician Medecin de famille canadien. 2017 Dec [PubMed PMID: 29237630]|
|||Przybilla B,Ring J,Völk M, [Total IgE levels in the serum in dermatologic diseases]. Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete. 1986 Feb [PubMed PMID: 3957665]|
|||Katayama C,Hayashida Y,Sugiyama S,Shiohara T,Aoyama Y, Corticosteroid-resistant prurigo nodularis: a rare syringotropic variant associated with hypohidrosis. European journal of dermatology : EJD. 2019 Mar 2; [PubMed PMID: 30827950]|
|||Legat FJ, The Antipruritic Effect of Phototherapy. Frontiers in medicine. 2018; [PubMed PMID: 30560129]|
|||Gupta MA,Pur DR,Vujcic B,Gupta AK, Use of antiepileptic mood stabilizers in dermatology. Clinics in dermatology. 2018 Nov - Dec; [PubMed PMID: 30446200]|
|||Beck KM,Yang EJ,Sekhon S,Bhutani T,Liao W, Dupilumab Treatment for Generalized Prurigo Nodularis. JAMA dermatology. 2019 Jan 1; [PubMed PMID: 30427994]|
|||Qureshi AA,Abate LE,Yosipovitch G,Friedman AJ, A systematic review of evidence-based treatments for prurigo nodularis. Journal of the American Academy of Dermatology. 2019 Mar; [PubMed PMID: 30261199]|
|||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 (Basel, Switzerland). 2013 [PubMed PMID: 24281309]|
|||Wong SS,Goh CL, Double-blind, right/left comparison of calcipotriol ointment and betamethasone ointment in the treatment of Prurigo nodularis. Archives of dermatology. 2000 Jun [PubMed PMID: 10871962]|
|||Patel T,Ishiuji Y,Yosipovitch G, Menthol: a refreshing look at this ancient compound. Journal of the American Academy of Dermatology. 2007 Nov [PubMed PMID: 17498839]|
|||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. Dermatologic therapy. 2014 May-Jun [PubMed PMID: 24102897]|
|||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. Journal of the European Academy of Dermatology and Venereology : JEADV. 2011 Jul [PubMed PMID: 20946583]|
|||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. The British journal of dermatology. 2010 Oct [PubMed PMID: 20491772]|
|||Wiznia LE,Callahan SW,Cohen DE,Orlow SJ, Rapid improvement of prurigo nodularis with cyclosporine treatment. Journal of the American Academy of Dermatology. 2018 Jun [PubMed PMID: 29438756]|
|||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. Journal of the European Academy of Dermatology and Venereology : JEADV. 2018 Mar [PubMed PMID: 29055135]|
|||Lear JT,English JS,Smith AG, Nodular prurigo responsive to azathioprine. The British journal of dermatology. 1996 Jun [PubMed PMID: 8763446]|
|||Gupta R, Treatment of prurigo nodularis with dexamethasone-cyclophosphamide pulse therapy. Indian journal of dermatology, venereology and leprology. 2016 Mar-Apr [PubMed PMID: 26924412]|
|||Halvorsen JA,Aasebø W, Oral tacrolimus treatment of pruritus in prurigo nodularis. Acta dermato-venereologica. 2015 Sep [PubMed PMID: 25804254]|
|||Feldmeyer L,Werner S,Kamarashev J,French LE,Hofbauer GF, Atopic prurigo nodularis responds to intravenous immunoglobulins. The British journal of dermatology. 2012 Feb [PubMed PMID: 21910702]|
|||Chen M,Doherty SD,Hsu S, Innovative uses of thalidomide. Dermatologic clinics. 2010 Jul [PubMed PMID: 20510766]|
|||Kanavy H,Bahner J,Korman NJ, Treatment of refractory prurigo nodularis with lenalidomide. Archives of dermatology. 2012 Jul [PubMed PMID: 22801610]|
|||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 dermato-venereologica. 2012 Sep [PubMed PMID: 22504709]|
|||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. Journal of dermatological science. 2010 Jun [PubMed PMID: 20417061]|
|||Waldinger TP,Wong RC,Taylor WB,Voorhees JJ, Cryotherapy improves prurigo nodularis. Archives of dermatology. 1984 Dec [PubMed PMID: 6508332]|
|||Stoll DM,Fields JP,King LE Jr, Treatment of prurigo nodularis: use of cryosurgery and intralesional steroids plus lidocaine. The Journal of dermatologic surgery and oncology. 1983 Nov [PubMed PMID: 6630706]|