Prurigo nodularis

INTRODUCTION — Prurigo nodularis (PN) is an uncommon, chronic skin disorder affecting primarily older adults and is characterized by symmetrically distributed, multiple, firm, pruritic nodules (picture 1A-B). PN occurs in patients with chronic pruritus and is frequently associated with a history of atopic dermatitis [1-3].

PN will be discussed in this topic. Chronic pruritus and other skin conditions associated with chronic pruritus and papulonodular skin lesions, including scabies and lichen planus, and acquired perforating dermatoses are discussed separately.

●(See "Pruritus: Etiology and patient evaluation".)

●(See "Scabies: Epidemiology, clinical features, and diagnosis".)

●(See "Lichen planus".)

●(See "Perforating dermatoses", section on 'Acquired perforating dermatosis'.)

EPIDEMIOLOGY — The exact incidence and prevalence of PN are not known. In the United States, the estimated prevalence is 72 per 100,000 persons [4]. PN can occur in all age groups without sex predilection but primarily affects older adults [5,6]. In a review of 108 cases of PN, the median age was 62 years [5]. In the United States, PN seems to be more common among African Americans than in other ethnic groups. In a single-institution study including 909 patients with PN, African American patients were 3.4 times more likely to have PN than White patients (odds ratio [OR] 3.4, 95% CI 2.9-3.9) [7].

PN occurs in approximately 5 percent of patients with human immunodeficiency virus (HIV) infection [8,9].

PATHOGENESIS — PN is a distinctive reaction pattern occurring in a subset of patients with chronic pruritus, as a result of continuous scratching over a prolonged period of time. Predisposing factors include dermatologic, systemic, neurologic, and psychiatric diseases associated with severe pruritus.

However, the exact pathogenesis of PN remains unclear. The following pathogenetic mechanisms have been hypothesized:

●Increased number of nerve fibers in the papillary dermis – Earlier studies noted an increased number of nerve fibers in the papillary dermis, suggesting a neurocutaneous component in the pathogenesis of PN [10]. Nerve growth factor (NGF) and its receptor, tyrosine kinase A (TrkA), are overexpressed in PN lesions and may be associated with the increased release and accumulation of neuropeptides, such as substance P and calcitonin gene-related peptide [11-13]. Mast cells, which are known to release NGF, are seen in close vicinity to nerves expressing TrkA [14,15].

●Cutaneous small fiber neuropathy – Subsequent studies have noted a hypoplasia of intraepidermal nerves in PN. An immunohistochemical study of 53 patients with PN found that intraepidermal nerve fiber density is reduced in lesional and nonlesional skin of patients with PN. A subsequent study of 30 patients with PN confirmed a significant reduction of intraepidermal nerve fiber density in lesional and perilesional skin compared with normal and healed skin. These findings suggest that PN may represent a form of subclinical, cutaneous small fiber neuropathy [16-18].

●Th2 cytokines – The role of T helper 1 (Th1) and T helper 2 (Th2) cytokines in the pathogenesis of PN also has been evaluated by examining the cytokine signatures in the epidermis in 22 cases of PN, using the signal transducers and activators of transcription (STAT) 1, 3, and 6 [19]. In 19 of 22 cases, the entire epidermis stained with anti-pSTAT 6, a marker for the Th2 cytokines interleukin (IL) 4, IL-5, and IL-13. Only eight cases showed scattered staining with anti-pSTAT 1, a marker for the Th1 cytokines interferon-gamma and IL-27. These findings suggest that Th2 cytokines play a principal role in the pathogenesis of PN.

A transcriptome analysis of lesional PN skin and blood immunophenotyping demonstrated circulating and cutaneous T helper type 22 (Th22) immune dysregulation skewed toward a Th22/IL-22 profile [20].

A proteomic analysis of plasma from patients with PN showed increased levels of inflammatory markers, including tumor necrosis factor (TNF), chemokine ligand (CXCL), IL-12B, IL-18, monocyte chemotactic protein, and TNF receptor superfamily member 9, compared with healthy controls [21]. The inflammatory protein profile also identified two clinically distinct clusters of patients with PN, one characterized by younger age and higher prevalence of myelopathy and the other characterized by higher prevalence of atopic dermatitis.

Aberrant expression of IL-31, a potent pruritogenic cytokine preferentially expressed by CD4+ Th2 cells, and other nonhistamine pruritogenic mediators, including NGF, thymic stromal lymphopoietin, and endothelin, has been described in PN lesions [22,23]. The receptor for IL-31, made up of two subunits (IL-31 receptor A [IL-31RA] and oncostatin M receptor-beta), is expressed on sensory neurons, keratinocytes, and myeloid cells. IL-31RA, expressed on a subset of small C-fiber neurons that innervate the skin from the dorsal root ganglion, is targeted by nemolizumab, a humanized monoclonal antibody.

Analysis of serum proteins comparing nemolizumab responders with nonresponders from a phase 2 trial showed downregulation of cytokines in the IL-6 family, which includes IL-31, confirming its role in the pathogenesis of at least some subtypes of PN [24].

HISTOPATHOLOGY — The histopathology of PN shows:

●Thick, compact orthohyperkeratosis.

●Irregular epidermal hyperplasia or pseudoepitheliomatous hyperplasia.

●Focal parakeratosis with irregular acanthosis.

●Diminished nerve fiber density.

●A nonspecific dermal infiltrate containing lymphocytes, macrophages, eosinophils, and neutrophils (picture 2) [25-28].

●A hair follicle may be seen in the center of the lesion [29].

CLINICAL MANIFESTATIONS — PN typically presents with firm, dome-shaped, itchy nodules ranging in size from a few millimeters to several centimeters and often symmetrically distributed on the extensor surfaces of the arms and legs and on the trunk (picture 1A-F). Nodules can be flesh-colored, erythematous, or brown/black and range in number from few to hundreds (picture 1B, 1G).

The extensor surfaces of the extremities are characteristically involved, but the upper back, abdomen, and sacrum can also be involved. The difficult-to-reach upper midback area is usually spared ("butterfly" sign (picture 3)) [28]. The palms, soles, face, and flexural areas are rarely involved.

Pruritus is always severe and distressing; it can be paroxysmal, sporadic, or continuous and is worsened by heat, sweating, or irritation from clothing. In many cases, the cause of pruritus is unknown. In a multicenter, cross-sectional, European study of 509 patients with PN, 71 percent of patients experience itch often or always and 53 percent reported that their daily life was negatively affected [30].

In some patients, a coexistent pruritic skin condition (eg, atopic dermatitis, xerosis) may be the initial cause of pruritus. Rarely, PN may be the presenting symptom of a systemic disease, such as infection with HIV or mycobacteria, parasitic infestation, or lymphoma [9,31-34].

A clinical presentation characterized by the coexistence of prurigo nodules and multiple keratoacanthomas on pruritic, actinically damaged skin has been described in several patients [35]. (See "Keratoacanthoma: Epidemiology, risk factors, and diagnosis".)

ASSOCIATED CONDITIONS — Approximately half of all cases of PN have a history of atopic dermatitis [5]. These patients may have PN at an earlier age than nonatopic patients [36]. (See "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis".)

Systemic diseases (eg, diabetes, chronic renal failure, cardiovascular disease, hepatitis C, gluten enteropathy, HIV infection), psychiatric disorders (eg, anxiety, depression), sleep disorders, and emotional stress have also been reported with high frequency in patients with PN [5,7,37-42]. PN occurs in approximately 5 percent of patients with HIV infection, particularly among individuals with a CD4+ count <200 cells/mm³ [8,9]. However, the exact role of these underlying conditions in the development of PN is unclear.

PN has also been associated with other conditions associated with alterations in central nervous system pain processing, such as fibromyalgia, interstitial cystitis/bladder pain syndrome, and irritable bowel syndrome. In an analysis of data on hospitalized patients from the National Inpatient Sample that included nearly 1500 patients with PN, patients with PN had increased odds of having fibromyalgia (odds ratio [OR] 3.38, 95% CI 2.78-4.10), interstitial cystitis/bladder pain syndrome (OR 24.40, 95% CI 19.42-30.64), and irritable bowel syndrome (OR 2.10, 95% CI 1.52-2.90) [43].

DIAGNOSIS — The diagnosis of PN is clinical, based upon a history of chronic, severe pruritus and the clinical finding of characteristic excoriated, nodular lesions often symmetrically distributed (picture 1C-E, 1G) [44]. A skin biopsy is not routinely performed to confirm the diagnosis.

However, a skin biopsy may be indicated in cases where the clinical diagnosis is in question or there is a poor response to first-line therapies. Immunofluorescence studies and enzyme-linked immunosorbent assay to detect the presence of circulating autoantibodies against bullous pemphigoid may be performed if suggested by history and clinical examination. (See 'Differential diagnosis' below.)

In patients with PN who do not have a history of atopic dermatitis or other pruritic skin conditions, systemic causes of chronic pruritus (eg, chronic kidney disease, liver disease, thyroid disease, HIV infection, parasitic infestation, malignancy) should be investigated. The initial laboratory and imaging evaluation may include (see "Pruritus: Etiology and patient evaluation"):

●Complete blood cell count

●Liver function tests

●Blood urea nitrogen and creatinine

●Thyroid-stimulating hormone

●HIV test

●Urinalysis

●Stool examination for ova and parasites

●Chest radiograph

DIFFERENTIAL DIAGNOSIS — Skin diseases that may mimic PN include:

●Acquired reactive perforating dermatoses – Acquired reactive perforating dermatoses are a group of rare skin disorders most commonly associated with chronic renal failure and diabetes mellitus, characterized by transepithelial elimination of dermal material. They present with pruritic, dome-shaped, umbilicated papules with a central keratinous plug located on the trunk and limbs (picture 4A-D) [45]. Histology reveals a cup-shaped depression of the epidermis filled with a plug consisting of keratin, collagen, and inflammatory debris. The underlying epidermis shows fine slits through which basophilic collagen fibers in vertical orientation are extruded. (See "Perforating dermatoses", section on 'Acquired perforating dermatosis'.)

●Pemphigoid nodularis – Pemphigoid nodularis is a rare variant of bullous pemphigoid (BP) characterized by pruritic nodules, papules, or plaques that mimic PN clinically and histologically [26,46]. The diagnosis is confirmed by direct immunofluorescence, showing linear immunoglobulin G (IgG) and/or complement component 3 (C3) staining along the basement membrane zone, and presence of circulating autoantibodies against BP antigens [46,47]. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid".)

●Nodular scabies – A history of exposure and histologic examination can usually differentiate PN from nodular scabies (picture 5A-C). Usually, other typical signs of scabies, such as burrows and excoriations, are present. (See "Scabies: Epidemiology, clinical features, and diagnosis", section on 'Diagnosis'.)

●Hypertrophic lichen planus – Hypertrophic lichen planus is a variant of lichen planus characterized by the presence of thick, hyperkeratotic plaques, often on the anterior aspect of the legs (picture 6). Histology can clarify the diagnosis. (See "Lichen planus".)

●Multiple keratoacanthomas – Multiple keratoacanthomas are a feature of several rare familial or sporadic disorders (table 1), including Ferguson-Smith syndrome and Grzybowski syndrome (picture 7) [48]. The absence of pruritus, histologic features, and clinical course differentiate multiple keratoacanthomas from PN. (See "Keratoacanthoma: Epidemiology, risk factors, and diagnosis", section on 'Multiple keratoacanthomas'.)

●Epidermolysis bullosa pruriginosa – Epidermolysis bullosa (EB) pruriginosa is a rare, localized variant of dystrophic EB characterized by skin fragility, intense pruritus, and skin lesions resembling hypertrophic lichen planus or PN [49,50]. The clinical suspicion of inherited EB needs to be confirmed by appropriate immunofluorescence studies. (See "Epidermolysis bullosa: Epidemiology, pathogenesis, classification, and clinical features", section on 'Rare subtypes'.)

MANAGEMENT — Treatment of PN is difficult and requires a multifaceted approach, involving [51]:

●Patient education to adopt general measures to reduce skin irritation and scratching

●Symptomatic treatment of pruritus

●Topical or systemic therapies aimed at interrupting the itch-scratch cycle and flattening the skin lesions

Topical and systemic therapies for PN have not been adequately evaluated in randomized trials. Evidence for their use is based upon a few small, randomized trials; small case series; and clinical experience [52].

Symptomatic control of pruritus — In patients with PN, gentle skin care using mild cleansers for bathing or showering and applying emollients multiple times per day to soothe the skin and reduce dryness should be encouraged. Additional relief can be provided by lotions that provide a cooling sensation on the skin, such as calamine lotion or lotions containing menthol and camphor, and those containing pramoxine hydrochloride, a local anesthetic.

To minimize the consequences of scratching and avoid excoriations, patients should keep their nails short and may wear gloves at night. Occluding the involved areas with bandages (eg, Unna boot) or dressings may provide further relief. (See "Compression therapy for the treatment of chronic venous insufficiency", section on 'Unna boot'.)

Any underlying compulsive behavior (eg, skin picking) should be treated. (See "Skin picking (excoriation) disorder and related disorders", section on 'General considerations'.)

Pharmacologic therapy with first-generation sedating antihistamines (eg, hydroxyzine, diphenhydramine) administered at bedtime may be useful in controlling nocturnal pruritus. Both selective serotonin reuptake inhibitors and tricyclic antidepressants are also employed for chronic pruritus, especially when a component of depression is present. (See "Pruritus: Therapies for localized pruritus".)

Limited disease

Topical and intralesional corticosteroids — For patients with a limited number of nodular lesions, we suggest superpotent topical corticosteroids (group 1 (table 2)) as first-line therapy. Topical corticosteroids, such as clobetasol dipropionate 0.05% ointment, are applied under occlusion with plastic wrap once at nighttime for at least two to four weeks, though a longer course of treatment may be needed. Twice-daily application is recommended if occlusion is not used. Once control is achieved, topical corticosteroids can be tapered to once or twice weekly and continued as a long-term maintenance regimen.

The efficacy of topical corticosteroids for the treatment of PN has not been adequately evaluated in randomized trials. In a single small study including 12 patients with PN, a betamethasone valerate 0.1% medicated tape was more effective than an anti-itch moisturizer in reducing the intensity of pruritus and provided the additional benefit of preventing scratching [53].

Based upon clinical experience, intralesional injection of corticosteroids is effective in reducing pruritus and flattening the nodules. It may be a treatment option in patients who have only a few large PN lesions. Triamcinolone acetonide in concentrations of 5 to 20 mg/mL (based upon the size of the lesion and response to therapy) is injected in the lesions every four weeks until pruritus subsides and the nodules are flattened. Once significant improvement is noted, intralesional corticosteroids can be discontinued. Early recurrences can be treated with superpotent topical corticosteroids. (See "Intralesional corticosteroid injection".)

Other topical therapies — Other topical treatments that have been used with some success in patients with limited PN include topical capsaicin, topical calcineurin inhibitors, and topical vitamin D analogues. None of these treatments has been adequately evaluated in randomized trials, and their use is based upon clinical experience and limited evidence from small observational studies.

Topical capsaicin may be a treatment option for motivated patients willing to adhere to a time-consuming schedule. Topical capsaicin 0.025% cream is applied four to six times per day for two weeks to up to several months, as tolerated.

Topical capsaicin exerts an analgesic and antipruritic effect by inducing the depletion of the neuropeptide substance P from local sensory nerve terminals in the skin, degeneration of epidermal nerve fibers, and desensitization of nociceptive nerve endings [54,55]. In one study, 33 patients with PN were treated with topical capsaicin 0.025 to 0.3% four to six times per day for 2 weeks up to 10 months [56]. Complete remission of pruritus was reported by all patients within 12 days of treatment. The nodules flattened and softened within two months in 24 patients. However, pruritus and skin nodules recurred in 16 patients upon discontinuation of treatment.

Other topical treatments reported as beneficial in small case series include topical tacrolimus, topical pimecrolimus, topical vitamin D analogues (eg, calcipotriol, tacalcitol), and a compounded mixture of topical ketamine, amitriptyline, and lidocaine [57-61].

Widespread or recalcitrant disease

Phototherapy — For patients with widespread disease and for those with recalcitrant disease that does not respond to topical or intralesional corticosteroids, we suggest narrowband ultraviolet B (NBUVB) phototherapy as first-line therapy if available and acceptable to the patient. NBUVB is administered two to three times weekly for up to 10 weeks in combination with topical corticosteroids. (See 'Topical and intralesional corticosteroids' above.)

Oral antihistamines, the tricyclic antidepressants doxepin or amitriptyline, or gabapentin/pregabalin may be given as adjunctive treatment to control pruritus. Emollients and topical corticosteroids may also be used as needed.

Psoralen plus ultraviolet A (PUVA) can be an alternative form of phototherapy if NBUVB is not available. (See "UVB phototherapy (broadband and narrowband)" and "Psoralen plus ultraviolet A (PUVA) photochemotherapy".)

Limited evidence for efficacy of phototherapy, including NBUVB, systemic and bath/topical PUVA, ultraviolet A1 (UVA1), and monochromatic 308 nm excimer light, for the treatment of PN is derived from small observational studies and a single randomized trial [62-67].

●In one study, 63 patients with PN were treated with topical PUVA [66]. Approximately 80 percent of patients improved after the first treatment cycle of two to four weeks.

●In another study, 22 patients with PN were randomized to use bath PUVA or bath PUVA plus targeted 308 nm excimer laser therapy. Six of 11 patients receiving bath PUVA alone and 7 of 10 receiving combined therapy had complete clearance [64]. Patients assigned to bath PUVA alone received an average of 20 treatment sessions, whereas patients assigned to combination therapy received an average of 10 bath PUVA sessions.

●NBUVB therapy was used to treat 10 patients with recalcitrant PN [67]. Improvement of skin lesions was reported in all patients after a median number of 16 weekly treatments.

●Monochromatic excimer light (308 nm) laser therapy induced partial or complete remission in 11 patients with PN after an average of 7.5 treatments [62].

●A modified Goeckerman regimen was successfully used in a small study of four patients with recalcitrant PN who had failed previous treatment with standard NBUVB and broadband UVB therapy [68]. The regimen consisted of daily broadband UVB therapy followed by application of crude coal tar and topical corticosteroids under occlusion for four hours.

Systemic therapies — Patients with widespread or recalcitrant PN who fail to respond to phototherapy and those for whom phototherapy is not feasible may benefit from systemic treatments. Dupilumab, an interleukin (IL) 4 receptor inhibitor that inhibits downstream signaling of IL-4 and IL-13, is effective in reducing pruritus and resolving the skin lesions in patients with recalcitrant PN. (See 'Dupilumab' below.)

Other systemic treatments include systemic immunosuppressants, thalidomide, lenalidomide, and anticonvulsants [69]. These treatments are associated with potential significant toxicity, and their efficacy in patients with recalcitrant PN has not been established.

Dupilumab — We suggest dupilumab as first-line systemic treatment for recalcitrant PN in adults, especially in patients with underlying atopic dermatitis. Dupilumab is administered subcutaneously at an initial dose of 600 mg, followed by 300 mg every other week. Dupilumab was approved by the US Food and Drug Administration for the treatment of PN in adults in September 2022 [70].

Multiple reports and two randomized trials have documented the efficacy of dupilumab in reducing pruritus and resolving the skin lesions in patients with recalcitrant PN [71-78].

In a phase 3 trial that included 151 adult patients with PN treated with dupilumab 300 mg every two weeks or placebo, more patients in the dupilumab group than those in the placebo group achieved a ≥4 point reduction in the Worst Itch Numeric Rating Scale (WI-NRS) at 24 weeks (60 versus 18 percent, respectively) [79]. A second identical phase 3 trial that enrolled 160 patients showed a ≥4 point reduction in WI-NRS in 37 percent of patients taking dupilumab compared with 22 percent of patients taking placebo at week 12 [79]. In both trials, more patients in the dupilumab groups achieved an Investigator Global Assessment (IGA) score of clear/almost clear at 24 weeks compared with patients in the placebo groups (48 versus 18 percent; and 45 versus 16 percent, respectively). Adverse events occurred with similar frequency in all groups, were in most cases nonserious, and did not lead to treatment interruption.

Conventional immunosuppressants — Low-dose methotrexate (at a dose of 7.5 to 20 mg per week) or oral cyclosporine (at a dose of 3 to 5 mg/kg per day) may be beneficial in patients with recalcitrant PN, based upon clinical experience and a few small observational studies.

In a series of 13 patients with PN resistant to conventional therapies, low-dose methotrexate (7.5 to 20 mg per week) was used for a minimum of six months. Ten patients achieved remission or marked improvement, measured as a reduction of the number and severity of skin lesions and pruritus [80].

Oral cyclosporine has been shown to induce rapid control of pruritus in patients with recalcitrant PN [81-83]. In one study including 14 patients treated with cyclosporine 3 to 5 mg/kg per day, 10 patients reported a "very good response" after an average treatment time of 2.7 months [82]. In another report, eight patients with PN refractory to multiple topical and systemic therapies were treated with cyclosporine 2 to 4 mg/kg per day for 2 to 48 months; six achieved remission (absence of active or new lesions) after the first two to four weeks of treatment [83]. However, long-term treatment with cyclosporine is limited by adverse effects, such as elevation of blood pressure and serum creatinine.

Thalidomide — In selected patients with refractory disease, a trial of thalidomide may be considered. However, thalidomide is teratogenic, and its use is associated with a dose-dependent risk of peripheral neuropathy that may be nonreversible, thromboembolism, and neutropenia. In the United States, patient and provider participation in the THALOMID Risk Evaluation and Mitigation Strategy (REMS) program is mandatory to obtain and dispense thalidomide.

Thalidomide is thought to have sedative, immunomodulatory, anti-inflammatory, and antiangiogenic properties [84]. Thalidomide has been used for the treatment of PN in both immunocompetent patients and in patients with HIV infection [85-90]. In a retrospective study, 42 patients with PN were treated with thalidomide at an average dose of 100 mg/day for an average of two years [86]. The average duration of thalidomide treatment before discontinuation due to neuropathy was 89 weeks (range: 1 week to 7.5 years). There was moderate to marked improvement in 50 percent of the patients; 12 patients showed only slight improvement or no effect.

Lenalidomide is a thalidomide analogue with more potent anti-inflammatory and antiangiogenic properties but with a reduced risk of peripheral neuropathy. Lenalidomide has been successfully used in a few patients with refractory PN [91-93].

Other — There are a few reports of successful treatment of recalcitrant PN with neuromodulators, such as gabapentin [94,95] and pregabalin [96-98], the mu-opioid receptor antagonist naltrexone [99], and a combination of montelukast and fexofenadine [100].

In an uncontrolled study including 20 patients (13 with PN) with intractable chronic pruritus, short-term treatment (<2 weeks) with aprepitant, a neurokinin receptor 1 antagonist, induced complete or partial resolution of pruritus in 12 patients [101]. However, in a subsequent randomized, cross-over trial including 58 patients with chronic PN, four-week treatment with aprepitant 80 mg per day was no more effective than placebo in reducing pruritus intensity in both intention-to-treat and per protocol analysis [102]. Nonsevere adverse events occurred with equal frequency in the aprepitant and placebo groups.

INVESTIGATIONAL THERAPIES

Nemolizumab — Nemolizumab is a humanized antihuman interleukin (IL) 31 receptor monoclonal antibody that inhibits the binding of IL-31 to its receptor and subsequent signal transduction. In phase 2 and 3 clinical trials, nemolizumab showed efficacy in reducing pruritus associated with atopic dermatitis [103-105].

●The efficacy of nemolizumab for the treatment of PN was evaluated in a randomized, phase 3 trial including 70 patients with moderate to severe PN (defined as presence of 20 or more nodules) and severe pruritus (defined as a mean score of at least 7 for the worst daily intensity of pruritus on a numerical rating scale of 0 to 10) for at least six months [106]. Patients received subcutaneous nemolizumab 0.5 mg/kg or placebo at baseline, week 4, and week 8. The primary outcome was the percent change from baseline in the peak pruritus score at week 4. Secondary outcomes included the reduction in the number of skin nodules at week 12. At week 4, the average peak pruritus score was reduced by 4.5 points (-53 percent) from baseline compared with a reduction by 1.7 points (-20 percent) in the placebo group (percentage difference 32.8, 95% CI -46.8 to -18.8). At week 12, the reduction in the mean lesion count was greater in the nemolizumab group than in the placebo group (least squares mean -12.6 versus -6.1 lesions, 95% CI -12.5 to -0.6). Adverse events associated with nemolizumab included abdominal pain, diarrhea, and musculoskeletal pain. A posthoc analysis of this trial showed that nemolizumab significantly reduced itch and improved sleep versus placebo within 48 hours [107].

●In a phase 3, randomized trial, 274 adult patients with moderate to severe PN were assigned to subcutaneous nemolizumab monotherapy (initial dose 60 mg followed by 30 or 60 mg every four weeks, based on body weight <90 or ≥90 kg) or matching placebo for 16 weeks [108]. At week 16, more patients receiving nemolizumab than those receiving placebo achieved the primary endpoints of itch improvement ≥4 points from baseline on the Peak Pruritus Numerical Rating Scale (53 versus 21 percent, respectively) and an Investigator Global Assessment (IGA) score of 0/1 (clear/almost clear; 38 versus 11 percent, respectively). Fewer patients in the nemolizumab group received rescue therapy compared with the placebo group (5 versus 15 percent, respectively). Overall, adverse events occurred in 61 percent of patients in the nemolizumab group and 53 percent of those in the placebo group. Adverse events reported with higher frequency in the nemolizumab group were exacerbation/new onset of atopic dermatitis and peripheral or facial edema.

Data on the long-term efficacy and safety of nemolizumab for PN are awaited.

Serlopitant — In a randomized trial including 128 patients with chronic, treatment-refractory PN, serlopitant, a novel oral neurokinin 1 (NK1) antagonist, given at the dose of 5 mg orally once daily for eight weeks was more effective than placebo in reducing the average itch visual analog scale scores (least squares mean difference [serlopitant minus placebo] was -1 at week 4 and -1.7 at week 8) [109]. Adverse events in the serlopitant group included nasopharyngitis, diarrhea, and fatigue.

PROGNOSIS — PN is a chronic and often intractable disease that may last for years, with a profound impact on the patient's quality of life. Complete resolution of lesions is rare, even after the itch-scratch cycle has been successfully interrupted. Recurrence is common.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Prurigo nodularis".)

SUMMARY AND RECOMMENDATIONS

●Clinical presentation – Prurigo nodularis (PN) is a chronic skin disorder characterized by multiple firm, itchy nodules typically localized to the extensor surface of the extremities (picture 1C-E, 1G). Pruritus is always severe and distressing; it can be paroxysmal, sporadic, or continuous and is worsened by heat, sweating, or irritation from clothing. (See 'Introduction' above and 'Clinical manifestations' above.)

●Diagnosis – The diagnosis of PN is clinical, based upon a history of chronic, severe pruritus and the clinical finding of characteristic excoriated, nodular lesions symmetrically distributed. Cutaneous and systemic causes of chronic pruritus should be investigated. (See 'Diagnosis' above and "Pruritus: Etiology and patient evaluation", section on 'Potential causes'.)

●Treatment – Treatment of PN is difficult and requires a multifaceted approach, involving patient education to adopt skin care measures to reduce skin irritation and scratching, symptomatic treatment of pruritus, and topical or systemic therapies aimed at interrupting the itch-scratch cycle and flattening the skin lesions. (See 'Management' above and 'Symptomatic control of pruritus' above.)

•Limited number of nodular lesions – For patients with a limited number of nodular lesions, we suggest superpotent topical corticosteroids (group 1 (table 2)) as first-line therapy (Grade 2C). Intralesional injection of corticosteroids may be an additional or alternative treatment modality for patients with very few lesions. Sedating antihistamines, such diphenhydramine, hydroxyzine, or others, are routinely used. (See 'Limited disease' above.)

•Widespread/recalcitrant disease – For patients with widespread or recalcitrant disease, we suggest phototherapy with narrowband ultraviolet B (NBUVB) as first-line therapy if available and acceptable to the patient (Grade 2C). (See 'Phototherapy' above.)

For patients for whom phototherapy is not feasible, we suggest treatment with dupilumab rather than other systemic agents (Grade 2C). Other systemic treatments include methotrexate, cyclosporine, thalidomide, gabapentin, and pregabalin. (See 'Systemic therapies' above and 'Dupilumab' above.)