Are You Confident of the Diagnosis?

What you should be alert for in the history

Patients complain of intermittent pruritus that is often severe. However, patients might not be pruritic. Be alert for symptoms or past medical history suggestive of underlying systemic disease; including drug addiction, which can present with pruritus and be confused with prurigo nodularis (PN). Look for evidence of an eruption that preceded the papule formation, since this might suggest a primary cutaneous eruption that the patient has scratched to the point of nodule formation.

Characteristic findings on physical examination

Characteristic clinical findings are few or many firm papules and nodules with hyperkeratosis, with or without excoriation, which tend to favor the extensor aspects of the extremities (Figure 1, Figure 2), although they can be found on the thorax, and even less commonly on the face and palms. There is often accompanying hyperpigmentation, hypopigmentation, excoriation, crusting, and/or lichenification.

Figure 1.


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Figure 2.

Prurigo papules.

It is important to do a thorough general skin examination looking for evidence of primary skin lesions, such as insect bite hypersensitivity reactions, folliculitis, acneiform eruptions, scabies, and papular or papulovesicular eruptions suggestive of dermatitis herpetiformis or bullous pemphigoid. Check for cervical, supraclavicular, axillary, and inguinal lymphadenopathy that might be indicative of underlying lymphoma. Excoriations without a history of pruritus should make the clinician suspicious of a psychological component to the patient’s prurigo.

Expected results of diagnostic studies

Biopsy usually demonstrates a superficial perivascular and/or interstitial lymphohistiocytic infiltrate, with neutrophils and eosinophils being present about 50% of the time. Fibrosis of the papillary dermis occurs more commonly than reticular dermal fibrosis. Irregular epidermal hyperplasia is seen more often than pseudoepitheliomatous hyperplasia. Usually, there is thick compact orthohyperkeratosis.

Hypergranulosis is present about half of the time. Focal parakeratosis and necrotic epidermal keratinocytes are seen less frequently. Neuronal hyperplasia and/or neuroma formation in the dermis has been reported with variable frequency in PN. The absence of neuronal hyperplasia, neuroma formation, and/or pseudoepitheliomatous hyperplasia does not rule out PN.

Rowland Payne found that half of patients with PN have a primary cutaneous disorder, the most common of which is atopic dermatitis. The remainder of patients with known causes of their itching have either underlying systemic disease or psychological causes. After atopic dermatitis, the most common cutaneous diseases associated with prurigo nodularis are nummular eczema, stasis dermatitis, insect bite hypersensitivity reactions, and folliculitis. Allergic contact dermatitis and subclinical variants of dermatitis herpetiformis or bullous pemphigoid also can be associated with PN.

Diagnosis confirmation

The differential diagnosis for discrete nodular lesions includes excoriated variants of the following skin disorders: insect bites, infestations, folliculitis (bacterial or fungal), other infections (sporotrichosis, nocardia, mycobacteria), infestations (nodular scabies), acneiform eruptions, vasculitis, multiple keratoacanthomas, hypertrophic lichen planus, bullous pemphigoid, and dermatitis herpetiformis. Biopsy is helpful in ruling out these disorders.

When infection is suspected, also ask for special staining with Gram, PAS, and Ziehl-Nielsen stains, as well as obtain a separate biopsy for culture. If pemphigoid nodularis or dermatitis herpetiformis are possible diagnoses, then perform a biopsy of lesional skin for routine histopathology and a biopsy of perilesional skin for direct immunofluorescence. Patch testing should be considered if the history and physical examination suggest the possibility of underlying allergic contact dermatitis, especially if the PN is accompanied by atopic dermatitis or another eczematous dermatitis.

Who is at Risk for Developing this Disease?

Prurigo nodularis can occur at any age, but tends to occur more often in adults, with fairly equal sex distribution.

What is the Cause of the Disease?

The cause of prurigo nodularis (PN) is not known. Although it might be a primary cutaneous disorder, it is often found to be a secondary cutaneous disorder developing after persistent scratching in response to a variety of causes.


The common biologic pathway by which these diseases give rise to prurigo papules and nodules is unclear. Substance P and calcitonin gene-related peptide are known mediators of neurogenic inflammation and pruritus, and immunohistochemical staining for both of these neuropeptides demonstrated an increased number of immunoreactive nerves in prurigo papules and nodules. Lesions of prurigo nodularis also contain increased numbers of mast cells and eosinophils, which are thought to release nerve growth factor (NGF) and eosinophilic granular basic proteins, respectively, into the skin of PN. NGF could contribute to the neural hyperplasia that is sometimes seen in PN. Alpha-MSH seen in the endothelial cells of PN affected skin may act to suppress local inflammation.

Another theory is that some cases of PN are part of a group of neurologic “sensor syndromes” in which abnormal CNS sensors or switches send inappropriate itch sensations to the periphery, much like the car engine light that tells you something is wrong despite the fact that a full evaluation of your car reveals otherwise. The patient keeps responding to this faulty signal by scratching to the point of producing skin lesions.

Systemic Implications and Complications

As has been seen in generalized pruritus, the most common systemic diseases associated with prurigo nodularis are disorders of the liver (hepatitis and obstructive biliary disease of various etiologies), blood (iron deficiency anemia, polycythemia vera, lymphoma, and leukemia), kidneys (renal insufficiency with uremia), and thyroid (hypothyroidism or hyperthyroidism). Infections (HIV, hepatitis B and C, streptococcal tonsillitis, colitis, intestinal parasites), gastrointestinal and other carcinomas, hypercalcemia, hyperparathyroidism, neurologic disorders (spinal cord injury), gluten-sensitive enteropathy, and alpha-1 antitrypsin deficiency also have been associated with PN.

For a small number of lesions, it is reasonable to treat with the first- line therapies noted below, and perform testing if the patient does not respond to conservative measures. In extensive or refractory cases, it is often best to obtain a biopsy for routine histopathology to look for evidence of primary cutaneous disorders like drug eruption, insect bite hypersensitivity reactions, allergic contact dermatitis, vasculitis, subclinical bullous pemphigoid or dermatitis herpetiformis. Based on your biopsy results and response to therapy, you may wish to consider biopsy for special stains and culture to rule out infection, and/or biopsy for direct immunofluorescence.

In addition, more extensive or refractory disease requires investigation to rule out systemic disease in much the same manner that you would approach generalized pruritus. The potential list of studies to perform can be endless, but the following tests should rule out the most common diseases that can be seen with prurigo nodularis: Complete blood count (CBC), erythrocyte sedimentation rate (ESR), blood urea nitrogen (BUN), creatinine, liver function tests (LFTs), thyroid stimlating hormone (TSH), iron saturation (Fe/TIBC or Fe/transferrin ratios), albumin, calcium, hepatitis B and C serologies, and chest xray.

Other tests to consider in the appropriate clinical settings include patch testing (especially if PN is accompanied by an eczematous dermatitis of unclear etiology), HIV serology, total serum IgE level (often elevated in atopic dermatitis), purified protein derivative (PPD) testing, parathyroid hormone level, and indirect immunofluoresence of serum to look for evidence of bullous pemphigoid, dermatitis herpetiformis, or celiac disease.

Positive results will alter therapy, and negative results help reassure the patient that they are not severely ill and allow the clinician to broach the possibility of a psychological component to the patient’s disease with more confidence and patient acceptance.

Treatment Options



-potent topical steroids with or without occlusion

-steroid impregnated tapes

-vitamin D analogues (calcipotriol or calcipotriene, tacalcitol)

-calcineurin inhibitors (tacrolimus and pimecrolimus)

-antipruritic lotions or creams containing menthol and phenol



-sedating oral antihistamines (hydroxyzine, promethazine, and others)




-roxithromycin and tranilast




-systemic corticosteroids





-intralesional steroid injections



-occlusive dressings (Duoderm locally, Unna boots or other dressings for extremities)

-phototherapy (broadband UVB, narrow band UVB, oral or topical PUVA, UVA1)

-excimer laser

-pulsed dye laser

Optimal Therapeutic Approach for this Disease

Treatment must be directed both at providing symptomatic relief from itching, and at discovering and treating the underlying cause of this disease. When a clear cause cannot be found, the possibility of underlying psychological disorders, such as anxiety and depression, must be addressed with the patient. If history suggests depression, anxiety, or obsessive-compulsive tendencies, then referral to a psychologist and/or psychiatrist is advised. When in doubt, it may be worth having the patient take one of the commercially available online psychological surveys to help better define the problem for the clinician and the patient.

If patients are resistant to obvious psychotherapeutic or psychiatric referral, then another approach is to refer them to a practitioner who “teaches techniques to help them stop scratching,” such as biofeedback, hypnosis, or habit reversal therapy. Explain that these techniques may help them ignore the faulty “car engine light” on their neurological dashboard. Psychological interventions also should be accompanied by medical, physical, and surgical therapies to provide symptom relief.

As xerosis tends to exacerbate pruritus and the eczematous diseases associated with prurigo nodularis, it is important to moisturize twice daily, in addition to the therapies discussed below. Topical antipruritics containing menthol and phenol may provide temporary immediate relief of itching, which can be important in giving the patient a sense of control, as can the brief application of ice packs to local areas. Avoid sensitizing topical anesthetic agents like benzocaine. Keep nails cut short and consider wearing gloves or mittens to bed.

Potent topical steroids (like clobetasol propionate) are the mainstay of therapy in PN, with or without occlusion. They are more effective when used under occlusion, which enhances their penetration. Steroid impregnated tapes, such as Cordran tape, are especially effective because they not only provide enhanced penetration of steroid but also prevent the patient from scratching individual lesions, thereby helping to break the scratch-itch cycle. Patients without access to steroid impregnated tapes can use duct tape or similar inexpensive over-the-counter products to occlude potent topical steroids with good success.

Intralesional steroids can be used for small numbers of treatment-resistant prurigo nodules. Start with triamcinolone acetonide 5mg/cc and increase the concentration by 5mg/cc per month up to 40mg/cc monthly as needed to clear individual lesions without causing cutaneous adverse side effects. Be careful to monitor patients frequently for cutaneous steroid side effects when using intralesional steroids or potent topical steroids, especially under occlusion.

Steroid sparing therapies will frequently need to be used in patients with chronic PN. Occlusive dressings alone have been found to be helpful. One case report notes excellent results with the use of Duoderm pads that were changed weekly by the physician. Temporarily wrapping severely affected extremities with Unna boots or similar dressings can be helpful. Vitamin D analogues and topical calcineurin inhibitors can be used alone or together with topical steroids. One strategy to reduce steroid side effects is to use potent topical steroids thrice weekly, while applying steroid-sparing therapies on all other days.

The topical vitamin D analogues calcipotriene (calcipotriol) and tacalcitol are reported to be safe and effective therapies for PN. In fact, calcipotriol ointment was shown to be more effective than betamethasone ointment in reducing the size and number of prurigo lesions in patients with PN. Therefore, it would seem reasonable to use combination therapy with topical steroids and topical vitamin D analogues to treat PN. A combination betamethasone and calcipotriene ointment is now available. Although not yet studied in the treatment of prurigo nodularis, the new vitamin D analogue calcitriol would be expected to be efficacious.

The topical calcineurin inhibitors tacrolimus and pimecrolimus have been studied in the treatment of PN. Efficacy was variable, with an average reduction in pruritus of 53% in one study. It is not surprising that thick nodules did not respond to therapy in this study. Occlusion of topical calcineurin inhibitors may be worthwhile for thicker lesions.

Capsaicin can be effective if applied 4-6 times daily. Initially, there may be erythema and a burning sensation appreciated in treated skin, but within 2 weeks inflammatory neuropeptides in the local sensory nerve terminals are depleted and itching resolves. However, the need to apply this medication so frequently and consistently makes it impractical, especially since itching often returns once the medication is discontinued.

Sedating oral antihistamines and antidepressants are best given several hours before bedtime to facilitate sleep and avoid excessive daytime drowsiness. If topical therapy does not make itching tolerable during the daytime, then oral antihistamines may be cautiously added to the treatment regimen during the day, but the prescribing physician must take into account and communicate the risk of oversedation and its consequences.

One pearl to minimizing the adverse effects of oversedation during antihistamine therapy is to prescribe hydroxyzine as 10 mg tablets, and instruct the patient to begin taking 2 to 3 tablets at bedtime, and then gradually titrate the dose as needed and as tolerated every few days (during which time some accommodation to the sedative effects usually occurs) until adequate control of pruritus is achieved without oversedation. Dosages of 50-100mg every 6 to 24 hours may be necessary. With one bottle of 10mg tablets, the patient has the flexibility to take a variety of lower doses during the day and higher doses at night. Rowland Payne has advoczated the use of promethazine 25-50 mg eleven hours before awakening.

Doxepin is a tricyclic antidepressant medication that has excellent antihistaminic properties, which makes it a superb antipuritic agent for people with depression. Dosages ranging from 10-50mg every bedtime have been reported to be effective in treating the pruritus of PN, although higher doses may be necessary to treat depression. Warn patients about the potential for oversedation and anticholinergic side effects such as constipation, dry mouth, urinary retention, and blurry vision. Because doxepin can prolong the Q-T interval, a pretreatment ECG is recommended in older patients and patients with known cardiac conduction abnormalities.

Gabapentin is an anticonvulsant that offers efficacy with a moderate side effect profile for PN therapy. There is no standard treatment regimen for PN, but one reported strategy is to start at 300mg/day and then gradually increase the dose by 300mg every 3 days (300mg daily, then 300mg twice daily, then 300mg thrice daily) until the minimal effective dose is achieved to control pruritus without excessive side effects. Treatment is continued for 3-4 months until the patient is clear or near clear, and then gradually tapered off. Sedation is the most common side effect, with hypersensitivity syndorme, pancytopenia, dyskinesia and cholestatsis occurring infrequently.

Naltrexone is a mu opioid receptor antagonist that has been used to treat chronic pruritus of varying origins. It has been used to treat PN in doses of 50-150mg/day. The most common side effects of mu opioid receptor antagonists are nausea, vomiting, diarrhea, dizziness, fatigue, and headache. These side effects are usually dose dependent, well tolerated, and worse during the first 2 weeks of therapy. Start with lower doses and gradually increase them if needed. Naltrexone is contraindicated in drug addicts, patients receiving opioid analgesics or opioid-containing medications, children, pregnant or breast feeding females, and patients with acute hepatitis, liver insufficiency, and hepatocellular disease.

Case reports using the combination of roxithromycin 300mg/day and tranilast 200mg/day report excellent improvement within 4-6 months of therapy. Roxithromycin is a macrolide antibiotic derived from erythromycin that is thought to inhibit TH2 cytokine release, while tranilast is an antiallergic drug capable of suppressing collagen synthesis from cutaneous fibroblasts.

Etretinate in doses of 50-75mg/day and the nonsteroidal antiinflammatory agent benoxaprofen also have been reported to help patients with PN.

Aprepitant is a neurokinin receptor (NKR1) antagonist that is thought to block substance P binding to the NKR1 receptor centrally and in the skin. It was found to be very effective in reducing pruritus in PN when given as monotherapy 80mg/day for an average of 1 week. Further study is needed to determine the optimal dose and duration of therapy.

Ultraviolet (UV) light therapy is a good choice to induce or maintain remission for patients with PN that is extensive and/or treatment resistant. Broadband and narrowband UVB, topical psoralen plus UVA (PUVA), oral PUVA, UVA1, and excimer light (308 nm) have been used alone, in combination with each other, and in combination with other oral and topical therapies to treat PN. The optimal therapy or dosing schedule has yet to be determined, and the physician should choose these therapies based on his or her expertise with them and their availability to the patient. Pulsed dye laser and excimer laser are better suited for more localized lesions of PN.

For a select group of patients, cryosurgery is an option. However, in order for cryosurgery to produce significant results, bullae formation is often required, which may lead to hypopigmentation and scarring, so that this therapy seems best reserved for isolated severely puruitic lesions that are refractory to other therapies in patients who accept the associated risks. Another approach is to lightly freeze a prurigo papule, wait until the lesion has thawed, and then inject it with triamcinolone.

When all else fails, or when very symptomatic patients with extensive disease need symptom relief for short periods of time while you are exploring or transitioning to safer therapies, consider systemic immunosuppressive therapy. Systemic steroids may be used alone or in conjunction with azathioprine, and then tapered off once azathioprine or topical therapies are able to control PN. Cyclosporine is highly effective in reducing pruritus and thereby promoting healing of prurigo lesions, especially in patients with an atopic diathesis. However, close monitoring is required because of the risks of renal damage and hypertension. This therapy is best suited for temporary treatment of severe extensive disabling prurigo nodularis that is not responding to less toxic therapies.

Thalidomide is very effective in treating PN in doses of 100mg – 400mg daily, but peripheral neuropathy occurs frequently and the drug is highly teratogenic. Therefore, some authors have advocated treatment with thalidomide doses in the range of 50-100mg daily for 3-6 months before considering the use of higher dosages. However, another promising approach is sequential combined treatment with thalidomide and narrow band UVB therapy, after which thalidomide is discontinued and the patient is maintained on narrow band UVB until clearance of lesions. Regardless of the treatment strategy, the side effects of thalidomide make this a treatment of last resort.

Patient Management

Initially see patients every 2-4 weeks, gradually progressing up the therapeutic ladder until relief of pruritus is achieved and/or the lesions clear. Before going to more toxic systemic therapies, it is advisable to use several less toxic therapies together to maximize clinical results. Once the patient is clear for several months, it is reasonable to begin tapering one therapy at a time as tolerated. Consider biopsy with culture before proceeding to immunosuppressive therapy. Don’t forget to keep reminding your patients of the importance of addressing any underlying psychological conditions with psychotherapy and/or behavioral techniques designed to reduce scratching.

Unusual Clinical Scenarios to Consider in Patient Management

HIV-infected patients with CD4 counts less than 200 have an increased prevalence of prurigo nodularis. Although the differential diagnosis is the same in all patients, certain diseases merit special attention in HIV infected patients with PN. Hepatitis C infection must be excluded. Insect bite reactions are exaggerated in these patients, as are opportunistic infections such as deep fungal and mycobacterial infections.

Pruritic dermatoses are common in HIV-infected patients and provide a background of pruritus within which PN can develop. Eosinophilic folliculitis and scabies are well suited to develop into prurigo papules. Therefore, biopsy for both routine histopathology and culture is recommended in HIV-infected patients. Since neoplasia is more common in this subset of patients, lymphoma and other malignancies should be ruled out. Finally, malabsorption, malnutrition, and psychological distress are important potential contributing factors to consider in this patient population. In addition to addressing the above mentioned issues, administering antiretroviral therapies, such as raltegravir, has been reported to improve PN in HIV-infected patients.

Patients on maintenance hemodialysis with PN should be evaluated for aluminium toxicity, since this subset of patients with refractory PN has been reported to improve greatly with the use of the aluminum chelating agent desferrioxamine.

Dermatitis herpetiformis and celiac disease should be treated with a gluten-free diet, and appropriate topical and systemic therapies as needed. These patients should be co-managed by a dermatologist and gastroenterologist, who should perform colonoscopies periodically because of the increased risk for gastrointestinal lymphomas in these patients.

Rarely, bullous pemphigoid is associated with prurigo nodularis and referred to as pemphigoid nodularis. Pemphigoid nodularis can precede the development of bullous pemphigoid. There is a case report of sulfamethoxypyridazine being used to treat this condition, although more standard therapies for bullous pemphigoid may be more appropriate.

What is the Evidence?

Rowland Payne, CME, Wilkinson, JD, McKee, PH, Jurecka, W, Black, MM. “Nodular prurigo–a clinicopathological study of 46 patients”. Br J Dermatol. 1985. pp. 431-39. (In this seminal review of 46 patients with PN, the authors summarize the clinical and histological features of PN, along with the most commonly associated cutaneous and systemic diseases, and psychological disorders.)

Weigelt, N, Metze, D, Stander, S. “Prurigo nodularis: systematic analysis of 58 histological criteria in 136 patients”. J Cutan Pathol. vol. 37. 2010. pp. 578-86. (The authors retrospectively evaluated skin biopsies from 136 patients diagnosed with PN and 45 patients diagnosed with lichen simplex chronicus for a large number of histological criteria, and identified the most characteristic histological findings of PN, which are detailed elsewhere in this chapter. Approximately 87% of these features also were found in lichen simplex chronicus, which supports the concept that these two diseases are part of a clinical spectrum.)

Wong, SS. “Double-blind , right/left comparison of calcipotriol ointment and betamethasone ointment in the treatment of prurigo nodularis”. Arch Dermatol. vol. 136. 2000. pp. 807-8. (Nine patients with PN completed treatment with twice-daily application of calcipotriol ointment 50 micrograms/gram to nodules on one leg while betamethasone valerate ointment 0.1% was applied to the nodules on the opposite leg for 8 weeks. Calcipotriol ointment led to faster reduction in lesion numbers and size than betamethasone valerate ointment. Subsequently, further improvement was noted when these patients were treated with calcipotriol ointment at night and betamethasone valerate ointment each morning for 2 more months, after which time three had complete remission and six had residual disease that could be treated with maintenance therapy with calcipotriol ointment.

Gencoglan, G, Inanir, I, Gunduz, K. Dermatol Ther. vol. 23. 2010. pp. 194-8. (Five patients with lichen simplex chronicus and four patients with PN were treated with gabapentin 300mg/day initially and gradually increased to 900mg/day for 4-10 months. Eight out of nine patients had a good response to therapy, with significantly decreased pruritus and partial to complete remission of lesions. The main side effect was sedation.)

Hann, SK, Cho, MY, Park, YK. “UV Treatment of generalized prurigo nodularis”. Int J Dermatol. vol. 29. 1990. pp. 436-7. (Two patients with extensive prurigo nodularis that did not respond to topical and intralesional steroids, and oral antihistamines were initially treated with UVB light therapy. Pruritus was significantly improved and most of their lesions cleared after 24 to 30 light treatments. Persistent lesions were subsequently treated with topical PUVA three times weekly for about 2 months, with further improvement of their disease to the point that any remaining pruritus or skin lesions could be maintained with weak topical steroids and oral antihistamine therapy.

Zelickson, BD, McEvoy, MT, Fransway, AF. “Patch testing in prurigo nodularis”. Contact Dermatitis. vol. 20. 1989. pp. 321-5. This review of the Mayo Clinic experience with patch testing of 32 prurigo nodularis patients from 1975-1987 revealed that 25 patients had positive reactions, with 11 of them being judged relevant to their PN. However, there may have been a selection bias, since these patients were referred for patch testing by dermatologists who felt that the patients' histories and physical exams were suspicious for contact dermatitis. Patients with preexisting or accompanying eczematous dermatitis were more likely to have positive patch test reactions.)

Orlando, A, Renna, S, Cottone, M. “Prurigo nodularis of Hyde treated with low-dose thalidomide”. Eur Rev Med Pharmacol Sci. vol. 13. 2009. pp. 141-5. (The authors advocate the use of low-dose thalidomide therapy to treat PN in order to minimize side effects. They report the case of a 52-year-old woman with extensive prurigo nodularis refractory to topical and oral therapy, who responded to thalidomide 100mg/day for 1 month followed by thalidomide 50mg and 100mg orally on alternating days. No neuropathy was noted after 6 months of thalidomide therapy.)