Article

The Diagnosis: Erythema Nodosum Leprosum

Erythema nodosum leprosum (ENL) is a type 2 reaction sometimes seen in patients infected with Mycobacterium leprae—primarily those with lepromatous or borderline lepromatous subtypes. Clinically, ENL manifests with abrupt onset of tender erythematous papules with associated fevers and general malaise. Studies have demonstrated a complex immune system reaction in ENL, but the detailed pathophysiology is not fully understood.¹ Biopsies conducted within 24 hours of lesion formation are most elucidating. Foamy histiocytes admixed with neutrophils are seen in the subcutis, often causing a lobular panniculitis (quiz image).² Neutrophils rarely are seen in other types of leprosy and thus are a useful diagnostic clue for ENL. Vasculitis of small- to medium-sized vessels can be seen but is not a necessary diagnostic criterion. Fite staining will highlight many acid-fast bacilli within the histiocytes (Figure 1).

Erythema nodosum leprosum is treated with a combination of immunosuppressants such as prednisone and thalidomide. Our patient was taking triple-antibiotic therapy—dapsone, rifampin, and clofazimine—for lepromatous leprosy when the erythematous papules developed on the arms and legs. After a skin biopsy confirmed the diagnosis of ENL, he was started on prednisone 20 mg daily with plans for close follow-up. Unfortunately, the patient was subsequently lost to follow-up.

Acute febrile neutrophilic dermatosis (also known as Sweet syndrome) is an acute inflammatory disease characterized by abrupt onset of painful erythematous papules, plaques, or nodules on the skin. It often is seen in association with preceding infections (especially those in the upper respiratory or gastrointestinal tracts), hematologic malignancies, inflammatory bowel disease, or exposure to certain classes of medications (eg, granulocyte colony-stimulating factor, tyrosine kinase inhibitors, various antibiotics).³ Histologically, acute febrile neutrophilic dermatosis is characterized by dense neutrophilic infiltrates, often with notable dermal edema (Figure 2).⁴ Many cases also show leukocytoclastic vasculitis; however, foamy histiocytes are not a notable component of the inflammatory infiltrate, though a histiocytoid form of acute febrile neutrophilic dermatosis has been described.⁵ Infections must be rigorously ruled out prior to diagnosing a patient with acute febrile neutrophilic dermatosis, making it a diagnosis of exclusion.

Cutaneous coccidioidomycosis is an infection caused by the dimorphic fungi Coccidioides immitis or Coccidioides posadasii. Cutaneous disease is rare but can occur from direct inoculation or dissemination from pulmonary disease in immunocompetent or immunocompromised patients. Papules, pustules, or plaques are seen clinically. Histologically, cutaneous coccidioidomycosis shows spherules that vary from 10 to 100 μm and are filled with multiple smaller endospores (Figure 3).⁶ Pseudoepitheliomatous hyperplasia with dense suppurative and granulomatous infiltrates also is seen.

Erythema induratum is characterized by tender nodules on the lower extremities and has a substantial female predominance. Many cases are associated with Mycobacterium tuberculosis infection. The bacteria are not seen directly in the skin but are instead detectable through DNA polymerase chain reaction testing or investigation of other organ systems.^7,8 Histologically, lesions show a lobular panniculitis with a mixed infiltrate. Vasculitis is seen in approximately 90% of erythema induratum cases vs approximately 25% of classic ENL cases (Figure 4),^2,9 which has led some to use the term nodular vasculitis to describe this disease entity. Nodular vasculitis is considered by others to be a distinct disease entity in which there are clinical and histologic features similar to erythema induratum but no evidence of M tuberculosis infection.⁹

Polyarteritis nodosa is a vasculitis that affects medium- sized vessels of various organ systems. The presenting signs and symptoms vary based on the affected organ systems. Palpable to retiform purpura, livedo racemosa, subcutaneous nodules, or ulcers are seen when the skin is involved. The histologic hallmark is necrotizing vasculitis of medium-sized arterioles (Figure 5), although leukocytoclastic vasculitis of small-caliber vessels also can be seen in biopsies of affected skin.¹⁰ The vascular changes are said to be segmental, with uninvolved segments interspersed with involved segments. Antineutrophil cytoplasmic antibody (ANCA)– associated vasculitis also must be considered when one sees leukocytoclastic vasculitis of small-caliber vessels in the skin, as it can be distinguished most readily by detecting circulating antibodies specific for myeloperoxidase (MPO-ANCA) or proteinase 3 (PR3-ANCA).

The Diagnosis: Erythema Nodosum Leprosum

Erythema nodosum leprosum (ENL) is a type 2 reaction sometimes seen in patients infected with Mycobacterium leprae—primarily those with lepromatous or borderline lepromatous subtypes. Clinically, ENL manifests with abrupt onset of tender erythematous papules with associated fevers and general malaise. Studies have demonstrated a complex immune system reaction in ENL, but the detailed pathophysiology is not fully understood.¹ Biopsies conducted within 24 hours of lesion formation are most elucidating. Foamy histiocytes admixed with neutrophils are seen in the subcutis, often causing a lobular panniculitis (quiz image).² Neutrophils rarely are seen in other types of leprosy and thus are a useful diagnostic clue for ENL. Vasculitis of small- to medium-sized vessels can be seen but is not a necessary diagnostic criterion. Fite staining will highlight many acid-fast bacilli within the histiocytes (Figure 1).

Erythema nodosum leprosum is treated with a combination of immunosuppressants such as prednisone and thalidomide. Our patient was taking triple-antibiotic therapy—dapsone, rifampin, and clofazimine—for lepromatous leprosy when the erythematous papules developed on the arms and legs. After a skin biopsy confirmed the diagnosis of ENL, he was started on prednisone 20 mg daily with plans for close follow-up. Unfortunately, the patient was subsequently lost to follow-up.

Acute febrile neutrophilic dermatosis (also known as Sweet syndrome) is an acute inflammatory disease characterized by abrupt onset of painful erythematous papules, plaques, or nodules on the skin. It often is seen in association with preceding infections (especially those in the upper respiratory or gastrointestinal tracts), hematologic malignancies, inflammatory bowel disease, or exposure to certain classes of medications (eg, granulocyte colony-stimulating factor, tyrosine kinase inhibitors, various antibiotics).³ Histologically, acute febrile neutrophilic dermatosis is characterized by dense neutrophilic infiltrates, often with notable dermal edema (Figure 2).⁴ Many cases also show leukocytoclastic vasculitis; however, foamy histiocytes are not a notable component of the inflammatory infiltrate, though a histiocytoid form of acute febrile neutrophilic dermatosis has been described.⁵ Infections must be rigorously ruled out prior to diagnosing a patient with acute febrile neutrophilic dermatosis, making it a diagnosis of exclusion.

Cutaneous coccidioidomycosis is an infection caused by the dimorphic fungi Coccidioides immitis or Coccidioides posadasii. Cutaneous disease is rare but can occur from direct inoculation or dissemination from pulmonary disease in immunocompetent or immunocompromised patients. Papules, pustules, or plaques are seen clinically. Histologically, cutaneous coccidioidomycosis shows spherules that vary from 10 to 100 μm and are filled with multiple smaller endospores (Figure 3).⁶ Pseudoepitheliomatous hyperplasia with dense suppurative and granulomatous infiltrates also is seen.

Erythema induratum is characterized by tender nodules on the lower extremities and has a substantial female predominance. Many cases are associated with Mycobacterium tuberculosis infection. The bacteria are not seen directly in the skin but are instead detectable through DNA polymerase chain reaction testing or investigation of other organ systems.^7,8 Histologically, lesions show a lobular panniculitis with a mixed infiltrate. Vasculitis is seen in approximately 90% of erythema induratum cases vs approximately 25% of classic ENL cases (Figure 4),^2,9 which has led some to use the term nodular vasculitis to describe this disease entity. Nodular vasculitis is considered by others to be a distinct disease entity in which there are clinical and histologic features similar to erythema induratum but no evidence of M tuberculosis infection.⁹

Polyarteritis nodosa is a vasculitis that affects medium- sized vessels of various organ systems. The presenting signs and symptoms vary based on the affected organ systems. Palpable to retiform purpura, livedo racemosa, subcutaneous nodules, or ulcers are seen when the skin is involved. The histologic hallmark is necrotizing vasculitis of medium-sized arterioles (Figure 5), although leukocytoclastic vasculitis of small-caliber vessels also can be seen in biopsies of affected skin.¹⁰ The vascular changes are said to be segmental, with uninvolved segments interspersed with involved segments. Antineutrophil cytoplasmic antibody (ANCA)– associated vasculitis also must be considered when one sees leukocytoclastic vasculitis of small-caliber vessels in the skin, as it can be distinguished most readily by detecting circulating antibodies specific for myeloperoxidase (MPO-ANCA) or proteinase 3 (PR3-ANCA).

The Diagnosis: Erythema Nodosum Leprosum

Erythema nodosum leprosum (ENL) is a type 2 reaction sometimes seen in patients infected with Mycobacterium leprae—primarily those with lepromatous or borderline lepromatous subtypes. Clinically, ENL manifests with abrupt onset of tender erythematous papules with associated fevers and general malaise. Studies have demonstrated a complex immune system reaction in ENL, but the detailed pathophysiology is not fully understood.¹ Biopsies conducted within 24 hours of lesion formation are most elucidating. Foamy histiocytes admixed with neutrophils are seen in the subcutis, often causing a lobular panniculitis (quiz image).² Neutrophils rarely are seen in other types of leprosy and thus are a useful diagnostic clue for ENL. Vasculitis of small- to medium-sized vessels can be seen but is not a necessary diagnostic criterion. Fite staining will highlight many acid-fast bacilli within the histiocytes (Figure 1).

Erythema nodosum leprosum is treated with a combination of immunosuppressants such as prednisone and thalidomide. Our patient was taking triple-antibiotic therapy—dapsone, rifampin, and clofazimine—for lepromatous leprosy when the erythematous papules developed on the arms and legs. After a skin biopsy confirmed the diagnosis of ENL, he was started on prednisone 20 mg daily with plans for close follow-up. Unfortunately, the patient was subsequently lost to follow-up.

Acute febrile neutrophilic dermatosis (also known as Sweet syndrome) is an acute inflammatory disease characterized by abrupt onset of painful erythematous papules, plaques, or nodules on the skin. It often is seen in association with preceding infections (especially those in the upper respiratory or gastrointestinal tracts), hematologic malignancies, inflammatory bowel disease, or exposure to certain classes of medications (eg, granulocyte colony-stimulating factor, tyrosine kinase inhibitors, various antibiotics).³ Histologically, acute febrile neutrophilic dermatosis is characterized by dense neutrophilic infiltrates, often with notable dermal edema (Figure 2).⁴ Many cases also show leukocytoclastic vasculitis; however, foamy histiocytes are not a notable component of the inflammatory infiltrate, though a histiocytoid form of acute febrile neutrophilic dermatosis has been described.⁵ Infections must be rigorously ruled out prior to diagnosing a patient with acute febrile neutrophilic dermatosis, making it a diagnosis of exclusion.

Cutaneous coccidioidomycosis is an infection caused by the dimorphic fungi Coccidioides immitis or Coccidioides posadasii. Cutaneous disease is rare but can occur from direct inoculation or dissemination from pulmonary disease in immunocompetent or immunocompromised patients. Papules, pustules, or plaques are seen clinically. Histologically, cutaneous coccidioidomycosis shows spherules that vary from 10 to 100 μm and are filled with multiple smaller endospores (Figure 3).⁶ Pseudoepitheliomatous hyperplasia with dense suppurative and granulomatous infiltrates also is seen.

Erythema induratum is characterized by tender nodules on the lower extremities and has a substantial female predominance. Many cases are associated with Mycobacterium tuberculosis infection. The bacteria are not seen directly in the skin but are instead detectable through DNA polymerase chain reaction testing or investigation of other organ systems.^7,8 Histologically, lesions show a lobular panniculitis with a mixed infiltrate. Vasculitis is seen in approximately 90% of erythema induratum cases vs approximately 25% of classic ENL cases (Figure 4),^2,9 which has led some to use the term nodular vasculitis to describe this disease entity. Nodular vasculitis is considered by others to be a distinct disease entity in which there are clinical and histologic features similar to erythema induratum but no evidence of M tuberculosis infection.⁹

Polyarteritis nodosa is a vasculitis that affects medium- sized vessels of various organ systems. The presenting signs and symptoms vary based on the affected organ systems. Palpable to retiform purpura, livedo racemosa, subcutaneous nodules, or ulcers are seen when the skin is involved. The histologic hallmark is necrotizing vasculitis of medium-sized arterioles (Figure 5), although leukocytoclastic vasculitis of small-caliber vessels also can be seen in biopsies of affected skin.¹⁰ The vascular changes are said to be segmental, with uninvolved segments interspersed with involved segments. Antineutrophil cytoplasmic antibody (ANCA)– associated vasculitis also must be considered when one sees leukocytoclastic vasculitis of small-caliber vessels in the skin, as it can be distinguished most readily by detecting circulating antibodies specific for myeloperoxidase (MPO-ANCA) or proteinase 3 (PR3-ANCA).

Prurigo nodularis (PN)(also called chronic nodular prurigo, prurigo nodularis of Hyde, or picker’s nodules) was first characterized by James Hyde in 1909.^1-3 Prurigo nodularis manifests with symmetrical, intensely pruritic, eroded, or hyperkeratotic nodules or papules on the extremities and trunk.^1,2,4,5 Studies have shown that individuals with PN experience pruritus, sleep loss, decreased social functioning from the appearance of the nodules, and a higher incidence of anxiety and depression, causing a negative impact on their quality of life.^2,6 In addition, the manifestation of PN has been linked to neurologic and psychiatric disorders; however, PN also can be idiopathic and manifest without underlying illnesses.^2,6,7

Prurigo nodularis has been associated with other dermatologic conditions such as atopic dermatitis (up to 50%), lichen planus, keratoacanthomas (KAs), and bullous pemphigoid.^7-9 It also has been linked to systemic diseases in 38% to 50% of cases, including chronic kidney disease, liver disease, type 2 diabetes mellitus, malignancies (hematopoietic, liver, and skin), and HIV infection.^6,8,10

The pathophysiology of PN is highly complex and has yet to be fully elucidated. It is thought to be due to dysregulation and interaction of the increase in neural and immunologic responses of proinflammatory and pruritogenic cytokines.^2,11 Treatments aim to break the itch-scratch cycle that perpetuates this disorder; however, this proves difficult, as PN is associated with a higher itch intensity than atopic dermatitis and psoriasis.¹⁰ Therefore, most patients attempt multiple forms of treatment for PN, ranging from topical therapies, oral immunosuppressants, and phototherapy to the newest and only medication approved by the US Food and Drug Administration for the treatment of PN—dupilumab.^1,7,11 Herein, we provide an updated review of PN with a focus on its epidemiology, histopathology and pathophysiology, comorbidities, clinical presentation, differential diagnosis, and current treatment options.

Epidemiology

There are few studies on the epidemiology of PN; however, middle-aged populations with underlying dermatologic or psychiatric disorders tend to be impacted most frequently.^2,12,13 In 2016, it was estimated that almost 88,000 individuals had PN in the United States, with the majority being female; however, this estimate only took into account those aged 18 to 64 years and utilized data from IBM MarketScan Commercial Claims and Encounters Database (IBM Watson Health) from October 2015 to December 2016.¹⁴ More recently, a retrospective database analysis estimated the prevalence of PN in the United States to be anywhere from 36.7 to 43.9 cases per 100,000 individuals. However, this retrospective review utilized the International Classification of Diseases, Tenth Revision code; PN has 2 codes associated with the diagnosis, and the coding accuracy is unknown.¹⁵ Sutaria et al¹⁶ looked at racial disparities in patients with PN utilizing data from TriNetX and found that patients who received a diagnosis of PN were more likely to be women, non-Hispanic, and Black compared with control patients. However, these estimates are restricted to the health care organizations within this database.

In 2018, Poland reported an annual prevalence of 6.52 cases per 100,000 individuals,¹⁷ while England reported a yearly prevalence of 3.27 cases per 100,000 individuals.¹⁸ Both countries reported most cases were female. However, these studies are not without limitations. Poland only uses the primary diagnosis code for medical billing to simplify clinical coding, thus underestimating the actual prevalence; furthermore, clinical codes more often than not are assigned by someone other than the diagnosing physician, leaving room for error.¹⁷ In addition, England’s PN estimate utilized diagnosis data from primary care and inpatient datasets, leaving out outpatient datasets in which patients with PN may have been referred and obtained the diagnosis, potentially underestimating the prevalence in this population.¹⁸

In contrast, Korea estimated the annual prevalence of PN to be 4.82 cases per 1000 dermatology outpatients, with the majority being men, based on results from a cross-sectional study among outpatients from the Catholic Medical Center. Although this is the largest health organization in Korea, the scope of this study is limited and lacks data from other medical centers in Korea.¹⁹

Histopathology and Pathophysiology

Almost all cells in the skin are involved in PN: keratinocytes, mast cells, dendritic cells, endothelial cells, lymphocytes, eosinophils, collagen fibers, and nerve fibers.^11,20 Classically, PN manifests as a dome-shaped lesion with hyperkeratosis, hypergranulosis, and psoriasiform epidermal hyperplasia with increased thickness of the papillary dermis consisting of coarse collagen with compact interstitial and circumvascular infiltration as well as increased lymphocytes and histocytes in the superficial dermis (Figure 1).²⁰ Hyperkeratosis is thought to be due to either the alteration of keratinocyte structures from scratching or keratinocyte abnormalities triggering PN.²¹ However, the increase in keratinocytes, which secrete nerve growth factor, allows for neuronal hyperplasia within the dermis.²² Nerve growth factor can stimulate keratinocyte proliferation²³ in addition to the upregulation of substance P (SP), a tachykinin that triggers vascular dilation and pruritus in the skin.²⁴ The density of SP nerve fibers in the dermis increases in PN, causing proinflammatory effects, upregulating the immune response to promote endothelial hyperplasia and increased vascularization.²⁵ The increase in these fibers may lead to pruritus associated with PN.^2,26

Many inflammatory cytokines and mediators also have been implicated in PN. Increased messenger RNA expression of IL-4, IL-17, IL-22, and IL-31 has been described in PN lesions.^3,27 Furthermore, studies also have reported increased helper T cell (T_H2) cytokines, including IL-4, IL-5, IL-10, and IL-13, in the dermis of PN lesions in patients without a history of atopy.^3,28 These pruritogenic cytokines in conjunction with the SP fibers may create an intractable itch for those with PN. The interaction and culmination of the neural and immune responses make PN a complex condition to treat with the multifactorial interaction of systems. 

Comorbidities

Prurigo nodularis has been associated with a wide array of comorbidities; however, the direction of the relationship between PN and these conditions makes it difficult to discern if PN is a primary or secondary condition.²⁹ Prurigo nodularis commonly has been connected to other inflammatory dermatoses, with a link to atopic dermatitis being the strongest.^5,29 However, PN also has been linked to other pruritic inflammatory cutaneous disorders, including psoriasis, cutaneous T-cell lymphoma, lichen planus, and dermatitis herpetiformis.^14,29

Huang et al¹⁴ found an increased likelihood of psychiatric illnesses in patients with PN, including eating disorders, nonsuicidal self-injury disorder, attention-deficit/hyperactivity disorder, schizophrenia, mood disorders, anxiety, and substance abuse disorders. Treatments directed at the neural aspect of PN have included selective serotonin reuptake inhibitors (SSRIs), which also are utilized to treat these mental health disorders.

Furthermore, systemic diseases also have been found to be associated with PN, including hypertension, type 2 diabetes mellitus, chronic kidney disease, heart failure, cerebrovascular disease, coronary heart disease, and chronic obstructive pulmonary disease.¹⁴ The relationship between PN and systemic conditions may be due to increased systemic inflammation and dysregulation of neural and metabolic functions implicated in these conditions from increased pruritic manifestations.^29,30 However, studies also have connected PN to infectious conditions such as HIV. One study found that patients with PN had 2.68 higher odds of infection with HIV compared to age- and sex-matched controls.¹⁴ It is unknown if these conditions contributed to the development of PN or PN contributed to the development of these disorders.

Clinical Presentations

Prurigo nodularis is a chronic inflammatory skin disease that typically manifests with multiple severely pruritic, dome-shaped, firm, hyperpigmented papulonodules with central scale or crust, often with erosion, due to chronic repetitive scratching and picking secondary to pruritic systemic or dermatologic diseases or psychological disorders (Figure 2).^1,2,4,5,8,31 Most often, diagnosis of PN is based on history and physical examination of the lesion; however, biopsies may be performed. These nodules commonly manifest with ulceration distributed symmetrically on extensor extremities in easy-to-reach places, sparing the mid back (called the butterfly sign).⁸ Lesions—either a few or hundreds—can range from a few millimeters to 2 to 3 cm.^8,32 The lesions differ in appearance depending on the pigment in the patient’s skin. In patients with darker skin tones, hyperpigmented or hypopigmented papulonodules are not uncommon, while those with fairer skin tones tend to present with erythema.³¹

Differential Diagnosis

Because of the variation in manifestation of PN, these lesions may resemble other cutaneous conditions. If the lesions are hyperkeratotic, they can mimic hypertrophic lichen planus, which mainfests with hyperkeratotic plaques or nodules on the lower extremities.^8,29 In addition, the histopathology of lichen planus resembles the appearance of PN, with epidermal hyperplasia, hypergranulosis, hyperkeratosis, and increased fibroblasts and capillaries.^8,29

Pemphigoid nodularis is a rare subtype of bullous pemphigoid that exhibits characteristics of PN with pruritic plaques and erosions.^8,29,33 The patient population for pemphigoid nodularis tends to be aged 50 to 60 years, and females are affected more frequently than males. However, pemphigoid nodularis may manifest with blistering and large plaques, which are not seen commonly with PN.²⁹ On histopathology, pemphigoid nodularis deposits IgG and C3 on the basement membrane and has subepidermal clefting, unlike PN.^7,29

Actinic prurigo manifests with pruritic papules or nodules post–UV exposure to unprotected skin.^8,29,33 This rare condition usually manifests with cheilitis and conjunctivitis. Unlike PN, which commonly affects elderly populations, actinic prurigo typically is found in young females.^8,29 Cytologic examination shows hyperkeratosis, spongiosis, and acanthosis of the epidermis with lymphocytic perivascular infiltration of the dermis.³⁴

Neurotic excoriations also tend to mimic PN with raised excoriated lesions; however, this disorder is due to neurotic picking of the skin without associated pruritus or true hyperkeratosis.^8,29,33 Histopathology shows epidermal crusting with inflammation of the upper dermis.³⁵

Infiltrative cutaneous squamous cell carcinoma (SCC) may imitate PN in appearance. It manifests as tender, ulcerated, scaly plaques or nodules. Histopathology shows cytologic atypia with an infiltrative architectural pattern and presence of collections of compact keratin and parakeratin (called keratin pearls).

Keratoacanthomas can resemble PN lesions. They usually manifest as nodules measuring 1 to 2 cm in diameter and 0.5 cm thick, resembling crateriform tumors.³⁶ On histopathology, KAs can resemble SCCs; however, KAs tend to manifest more frequently with a keratin-filled crater with a ground-glass appearance.³⁶

Inverted follicular keratosis commonly manifests on the face in elderly men as a single, flesh-colored, verrucous papule that may resemble PN. However, cytology of inverted follicular keratosis is characterized by proliferation and squamous eddies.³⁷ Consideration of the histologic findings and clinical appearance are important to differentiate between PN and cutaneous SCC.

Pseudoepitheliomatous hyperplasia is a benign condition that manifests as a plaque or nodule with crust, scale, or ulceration. Histologically, this condition presents with hyperplastic proliferation of the epidermis and adnexal epithelium.³⁸ The clinical and histologic appearance can mimic PN and other cutaneous eruptions with epidermal hyperplasia. 

In clinical cases that are resistant to treatment, biopsy is the best approach to diagnose the lesion. Due to similarities in physical appearance and superficial histologic presentation of PN, KAs from SCC, hypertrophic lichen planus, and other hyperkeratotic lesions, the biopsy should be taken at the base of the lesion to sample deeper layers of skin to differentiate these dermatologic disorders.

Management

Current treatments for PN yield varied results. Many patients with moderate to severe PN attempt multiple therapies before seeing improvement.³¹ Treatments include topical, oral, and injectable medications and are either directed at the neural or immune components of PN due to the interplay between increased nerve fibers in the lesions (neural axis) as well as increases in cytokines and other immunologic mediators (immune axis) of this condition. However, the FDA recently approved the first treatment for PN—dupilumab—which is an injectable IL-4 receptor antagonist directed at the immunologic interactions affiliated with PN.

Immune-Mediated Topical Therapies—Immunologic topical therapies include corticosteroids, calcipotriol, and calcineurin inhibitors. Studies that have analyzed these treatments are limited to case reports and small intraindividual and randomized controlled trials (Table 1). Topical therapies usually are first-line agents for most patients. Adverse effects include transient irritation of the skin.^40,42,43

Supplements—N-acetyl cysteine is an over-the-counter supplement that has been reported to improve symptoms in patients with skin-picking disorders.⁴⁸ The mechanism of action includes antioxidant effects such as decreasing reactive oxygen species, decreasing inflammatory markers, regulating neurotransmitters, and inhibiting hyperkeratosis.⁴⁹ N-acetyl cysteine has been poorly studied for its application in PN. A small study of 3 patients with subacute PN receiving 1200 mg of oral N-acetyl cysteine reported varying levels of improvement in skin appearance and reduction in skin picking.⁵⁰

Phototherapy—Phototherapy, a typical first- or second-line treatment modality for PN, targets both the neural- and immune-mediated aspects associated with pruritus in PN (Table 1).⁵¹ UV light can penetrate through the epidermal layer of the skin and reach the keratinocytes, which play a role in the immune-related response of PN. In addition, the cutaneous sensory nerves are located in the upper dermal layer, from which nerve fibers grow and penetrate into the epidermis, thereby interacting with the keratinocytes where pruritic signals are transmitted from the periphery up to the brain.⁵¹

Studies analyzing the effects of phototherapy on PN are limited to case series and a small randomized controlled trial. However, this trial has shown improvements in pruritus in the participants. Adverse effects include transient burning and erythema at the treated sites.^44,45

Immune-Mediated Oral Therapies—Immunologic-targeted oral therapies include bilastine, methotrexate, and cyclosporine (Table 2).^52,53 Bilastine efficacy was analyzed in a small phase 3, open-label, multicenter study in Japan; however, patients were allowed to use topical steroids in conjunction with the oral antihistamine.⁵⁴ Methotrexate and cyclosporine are immunosuppressive medications and were analyzed in small retrospective studies. Both treatments yielded notable relief for patients; however, 38.5% (15/39) of patients receiving methotrexate experienced adverse events, and 50.0% (4/8) experienced adverse events with cyclosporine.^52,53

Thalidomide was studied in a small retrospective case review that showed notable improvement in PN. Dosages of thalidomide varied, but on average the dose was 100 mg/d. However, greater than 50% of patients experienced at least 1 adverse effect with this treatment.⁶³

A study performed in Italy showed promising results for patients treated with pregabalin, with 70.0% (21/30) continuing to take pregabalin for almost 2 years following completion of the initial 3-month trial.⁵⁵ Naltrexone decreased pruritus in more than half of patients (9/17).⁵⁹ Amitriptyline yielded improvements in patients with PN; however, disease recurred in 5 patients (29%) after 7 months.⁶² A study performed in Germany reported promising results for paroxetine and fluvoxamine; however, some patients enrolled in the study had some form of psychiatric disorder.⁶¹

Serlopitant, aprepitant, and nalbuphine were studied in randomized controlled trials. The serlopitant trials were the largest of the neurally mediated oral medication studies; one showed substantial improvement in patients with PN,⁵⁶ while the most recent trial did not show significant improvement (ClinicalTrials.gov identifier NCT03546816).⁵⁷ On the other hand, aprepitant showed no major difference between the experimental and placebo groups.⁵⁸ Nalbuphine 162 mg twice daily showed greater improvement in PN than nalbuphine 81 mg twice daily.⁶⁰

Immune-Mediated Injectable Therapies—Immune-targeted injectables include nemolizumab and dupilumab (Table 2). Nemolizumab is an IL-31 antagonist that has been studied in a small randomized controlled trial that showed great success in decreasing pruritus associated with PN.⁶⁴ IL-31 has been implicated in PN, and inhibition of the IL-31 receptor has been shown to disrupt the itch-scratch cycle of PN. Dupilumab is a monoclonal antibody against the IL-4 and IL-13 receptors, and it is the only FDA-approved treatment for PN.⁶⁵ Blockage of these protein receptors decreases type 2 inflammation and chronic pruritus.^66,67 Dupilumab is FDA approved for the treatment of atopic dermatitis and recently was approved for adults with PN. Dupilumab acts to block the shared α-subunit of the pruritogenic cytokines IL-4 and IL-13 pathways,²⁹ thereby breaking the itch-scratch cycle associated with PN and allowing for the healing of these lesions. Results from 2 clinical trials showed substantially reduced itch in patients with PN.⁶⁵ Dupilumab also was approved by the European Medicines Agency for moderate to severe PN.⁶⁸

Conclusion

Prurigo nodularis is a chronic condition that affects patient quality of life and can mimic various dermatologic conditions. The epidemiology and pathophysiology of PN have not been fully expounded. More research should be conducted to determine the underpinnings of PN to help identify more consistently effective therapies for this complex condition.

Prurigo nodularis (PN)(also called chronic nodular prurigo, prurigo nodularis of Hyde, or picker’s nodules) was first characterized by James Hyde in 1909.^1-3 Prurigo nodularis manifests with symmetrical, intensely pruritic, eroded, or hyperkeratotic nodules or papules on the extremities and trunk.^1,2,4,5 Studies have shown that individuals with PN experience pruritus, sleep loss, decreased social functioning from the appearance of the nodules, and a higher incidence of anxiety and depression, causing a negative impact on their quality of life.^2,6 In addition, the manifestation of PN has been linked to neurologic and psychiatric disorders; however, PN also can be idiopathic and manifest without underlying illnesses.^2,6,7

Prurigo nodularis has been associated with other dermatologic conditions such as atopic dermatitis (up to 50%), lichen planus, keratoacanthomas (KAs), and bullous pemphigoid.^7-9 It also has been linked to systemic diseases in 38% to 50% of cases, including chronic kidney disease, liver disease, type 2 diabetes mellitus, malignancies (hematopoietic, liver, and skin), and HIV infection.^6,8,10

The pathophysiology of PN is highly complex and has yet to be fully elucidated. It is thought to be due to dysregulation and interaction of the increase in neural and immunologic responses of proinflammatory and pruritogenic cytokines.^2,11 Treatments aim to break the itch-scratch cycle that perpetuates this disorder; however, this proves difficult, as PN is associated with a higher itch intensity than atopic dermatitis and psoriasis.¹⁰ Therefore, most patients attempt multiple forms of treatment for PN, ranging from topical therapies, oral immunosuppressants, and phototherapy to the newest and only medication approved by the US Food and Drug Administration for the treatment of PN—dupilumab.^1,7,11 Herein, we provide an updated review of PN with a focus on its epidemiology, histopathology and pathophysiology, comorbidities, clinical presentation, differential diagnosis, and current treatment options.

Epidemiology

There are few studies on the epidemiology of PN; however, middle-aged populations with underlying dermatologic or psychiatric disorders tend to be impacted most frequently.^2,12,13 In 2016, it was estimated that almost 88,000 individuals had PN in the United States, with the majority being female; however, this estimate only took into account those aged 18 to 64 years and utilized data from IBM MarketScan Commercial Claims and Encounters Database (IBM Watson Health) from October 2015 to December 2016.¹⁴ More recently, a retrospective database analysis estimated the prevalence of PN in the United States to be anywhere from 36.7 to 43.9 cases per 100,000 individuals. However, this retrospective review utilized the International Classification of Diseases, Tenth Revision code; PN has 2 codes associated with the diagnosis, and the coding accuracy is unknown.¹⁵ Sutaria et al¹⁶ looked at racial disparities in patients with PN utilizing data from TriNetX and found that patients who received a diagnosis of PN were more likely to be women, non-Hispanic, and Black compared with control patients. However, these estimates are restricted to the health care organizations within this database.

In 2018, Poland reported an annual prevalence of 6.52 cases per 100,000 individuals,¹⁷ while England reported a yearly prevalence of 3.27 cases per 100,000 individuals.¹⁸ Both countries reported most cases were female. However, these studies are not without limitations. Poland only uses the primary diagnosis code for medical billing to simplify clinical coding, thus underestimating the actual prevalence; furthermore, clinical codes more often than not are assigned by someone other than the diagnosing physician, leaving room for error.¹⁷ In addition, England’s PN estimate utilized diagnosis data from primary care and inpatient datasets, leaving out outpatient datasets in which patients with PN may have been referred and obtained the diagnosis, potentially underestimating the prevalence in this population.¹⁸

In contrast, Korea estimated the annual prevalence of PN to be 4.82 cases per 1000 dermatology outpatients, with the majority being men, based on results from a cross-sectional study among outpatients from the Catholic Medical Center. Although this is the largest health organization in Korea, the scope of this study is limited and lacks data from other medical centers in Korea.¹⁹

Histopathology and Pathophysiology

Almost all cells in the skin are involved in PN: keratinocytes, mast cells, dendritic cells, endothelial cells, lymphocytes, eosinophils, collagen fibers, and nerve fibers.^11,20 Classically, PN manifests as a dome-shaped lesion with hyperkeratosis, hypergranulosis, and psoriasiform epidermal hyperplasia with increased thickness of the papillary dermis consisting of coarse collagen with compact interstitial and circumvascular infiltration as well as increased lymphocytes and histocytes in the superficial dermis (Figure 1).²⁰ Hyperkeratosis is thought to be due to either the alteration of keratinocyte structures from scratching or keratinocyte abnormalities triggering PN.²¹ However, the increase in keratinocytes, which secrete nerve growth factor, allows for neuronal hyperplasia within the dermis.²² Nerve growth factor can stimulate keratinocyte proliferation²³ in addition to the upregulation of substance P (SP), a tachykinin that triggers vascular dilation and pruritus in the skin.²⁴ The density of SP nerve fibers in the dermis increases in PN, causing proinflammatory effects, upregulating the immune response to promote endothelial hyperplasia and increased vascularization.²⁵ The increase in these fibers may lead to pruritus associated with PN.^2,26

Many inflammatory cytokines and mediators also have been implicated in PN. Increased messenger RNA expression of IL-4, IL-17, IL-22, and IL-31 has been described in PN lesions.^3,27 Furthermore, studies also have reported increased helper T cell (T_H2) cytokines, including IL-4, IL-5, IL-10, and IL-13, in the dermis of PN lesions in patients without a history of atopy.^3,28 These pruritogenic cytokines in conjunction with the SP fibers may create an intractable itch for those with PN. The interaction and culmination of the neural and immune responses make PN a complex condition to treat with the multifactorial interaction of systems. 

Comorbidities

Prurigo nodularis has been associated with a wide array of comorbidities; however, the direction of the relationship between PN and these conditions makes it difficult to discern if PN is a primary or secondary condition.²⁹ Prurigo nodularis commonly has been connected to other inflammatory dermatoses, with a link to atopic dermatitis being the strongest.^5,29 However, PN also has been linked to other pruritic inflammatory cutaneous disorders, including psoriasis, cutaneous T-cell lymphoma, lichen planus, and dermatitis herpetiformis.^14,29

Huang et al¹⁴ found an increased likelihood of psychiatric illnesses in patients with PN, including eating disorders, nonsuicidal self-injury disorder, attention-deficit/hyperactivity disorder, schizophrenia, mood disorders, anxiety, and substance abuse disorders. Treatments directed at the neural aspect of PN have included selective serotonin reuptake inhibitors (SSRIs), which also are utilized to treat these mental health disorders.

Furthermore, systemic diseases also have been found to be associated with PN, including hypertension, type 2 diabetes mellitus, chronic kidney disease, heart failure, cerebrovascular disease, coronary heart disease, and chronic obstructive pulmonary disease.¹⁴ The relationship between PN and systemic conditions may be due to increased systemic inflammation and dysregulation of neural and metabolic functions implicated in these conditions from increased pruritic manifestations.^29,30 However, studies also have connected PN to infectious conditions such as HIV. One study found that patients with PN had 2.68 higher odds of infection with HIV compared to age- and sex-matched controls.¹⁴ It is unknown if these conditions contributed to the development of PN or PN contributed to the development of these disorders.

Clinical Presentations

Prurigo nodularis is a chronic inflammatory skin disease that typically manifests with multiple severely pruritic, dome-shaped, firm, hyperpigmented papulonodules with central scale or crust, often with erosion, due to chronic repetitive scratching and picking secondary to pruritic systemic or dermatologic diseases or psychological disorders (Figure 2).^1,2,4,5,8,31 Most often, diagnosis of PN is based on history and physical examination of the lesion; however, biopsies may be performed. These nodules commonly manifest with ulceration distributed symmetrically on extensor extremities in easy-to-reach places, sparing the mid back (called the butterfly sign).⁸ Lesions—either a few or hundreds—can range from a few millimeters to 2 to 3 cm.^8,32 The lesions differ in appearance depending on the pigment in the patient’s skin. In patients with darker skin tones, hyperpigmented or hypopigmented papulonodules are not uncommon, while those with fairer skin tones tend to present with erythema.³¹

Differential Diagnosis

Because of the variation in manifestation of PN, these lesions may resemble other cutaneous conditions. If the lesions are hyperkeratotic, they can mimic hypertrophic lichen planus, which mainfests with hyperkeratotic plaques or nodules on the lower extremities.^8,29 In addition, the histopathology of lichen planus resembles the appearance of PN, with epidermal hyperplasia, hypergranulosis, hyperkeratosis, and increased fibroblasts and capillaries.^8,29

Pemphigoid nodularis is a rare subtype of bullous pemphigoid that exhibits characteristics of PN with pruritic plaques and erosions.^8,29,33 The patient population for pemphigoid nodularis tends to be aged 50 to 60 years, and females are affected more frequently than males. However, pemphigoid nodularis may manifest with blistering and large plaques, which are not seen commonly with PN.²⁹ On histopathology, pemphigoid nodularis deposits IgG and C3 on the basement membrane and has subepidermal clefting, unlike PN.^7,29

Actinic prurigo manifests with pruritic papules or nodules post–UV exposure to unprotected skin.^8,29,33 This rare condition usually manifests with cheilitis and conjunctivitis. Unlike PN, which commonly affects elderly populations, actinic prurigo typically is found in young females.^8,29 Cytologic examination shows hyperkeratosis, spongiosis, and acanthosis of the epidermis with lymphocytic perivascular infiltration of the dermis.³⁴

Neurotic excoriations also tend to mimic PN with raised excoriated lesions; however, this disorder is due to neurotic picking of the skin without associated pruritus or true hyperkeratosis.^8,29,33 Histopathology shows epidermal crusting with inflammation of the upper dermis.³⁵

Infiltrative cutaneous squamous cell carcinoma (SCC) may imitate PN in appearance. It manifests as tender, ulcerated, scaly plaques or nodules. Histopathology shows cytologic atypia with an infiltrative architectural pattern and presence of collections of compact keratin and parakeratin (called keratin pearls).

Keratoacanthomas can resemble PN lesions. They usually manifest as nodules measuring 1 to 2 cm in diameter and 0.5 cm thick, resembling crateriform tumors.³⁶ On histopathology, KAs can resemble SCCs; however, KAs tend to manifest more frequently with a keratin-filled crater with a ground-glass appearance.³⁶

Inverted follicular keratosis commonly manifests on the face in elderly men as a single, flesh-colored, verrucous papule that may resemble PN. However, cytology of inverted follicular keratosis is characterized by proliferation and squamous eddies.³⁷ Consideration of the histologic findings and clinical appearance are important to differentiate between PN and cutaneous SCC.

Pseudoepitheliomatous hyperplasia is a benign condition that manifests as a plaque or nodule with crust, scale, or ulceration. Histologically, this condition presents with hyperplastic proliferation of the epidermis and adnexal epithelium.³⁸ The clinical and histologic appearance can mimic PN and other cutaneous eruptions with epidermal hyperplasia. 

In clinical cases that are resistant to treatment, biopsy is the best approach to diagnose the lesion. Due to similarities in physical appearance and superficial histologic presentation of PN, KAs from SCC, hypertrophic lichen planus, and other hyperkeratotic lesions, the biopsy should be taken at the base of the lesion to sample deeper layers of skin to differentiate these dermatologic disorders.

Management

Current treatments for PN yield varied results. Many patients with moderate to severe PN attempt multiple therapies before seeing improvement.³¹ Treatments include topical, oral, and injectable medications and are either directed at the neural or immune components of PN due to the interplay between increased nerve fibers in the lesions (neural axis) as well as increases in cytokines and other immunologic mediators (immune axis) of this condition. However, the FDA recently approved the first treatment for PN—dupilumab—which is an injectable IL-4 receptor antagonist directed at the immunologic interactions affiliated with PN.

Immune-Mediated Topical Therapies—Immunologic topical therapies include corticosteroids, calcipotriol, and calcineurin inhibitors. Studies that have analyzed these treatments are limited to case reports and small intraindividual and randomized controlled trials (Table 1). Topical therapies usually are first-line agents for most patients. Adverse effects include transient irritation of the skin.^40,42,43

Supplements—N-acetyl cysteine is an over-the-counter supplement that has been reported to improve symptoms in patients with skin-picking disorders.⁴⁸ The mechanism of action includes antioxidant effects such as decreasing reactive oxygen species, decreasing inflammatory markers, regulating neurotransmitters, and inhibiting hyperkeratosis.⁴⁹ N-acetyl cysteine has been poorly studied for its application in PN. A small study of 3 patients with subacute PN receiving 1200 mg of oral N-acetyl cysteine reported varying levels of improvement in skin appearance and reduction in skin picking.⁵⁰

Phototherapy—Phototherapy, a typical first- or second-line treatment modality for PN, targets both the neural- and immune-mediated aspects associated with pruritus in PN (Table 1).⁵¹ UV light can penetrate through the epidermal layer of the skin and reach the keratinocytes, which play a role in the immune-related response of PN. In addition, the cutaneous sensory nerves are located in the upper dermal layer, from which nerve fibers grow and penetrate into the epidermis, thereby interacting with the keratinocytes where pruritic signals are transmitted from the periphery up to the brain.⁵¹

Studies analyzing the effects of phototherapy on PN are limited to case series and a small randomized controlled trial. However, this trial has shown improvements in pruritus in the participants. Adverse effects include transient burning and erythema at the treated sites.^44,45

Immune-Mediated Oral Therapies—Immunologic-targeted oral therapies include bilastine, methotrexate, and cyclosporine (Table 2).^52,53 Bilastine efficacy was analyzed in a small phase 3, open-label, multicenter study in Japan; however, patients were allowed to use topical steroids in conjunction with the oral antihistamine.⁵⁴ Methotrexate and cyclosporine are immunosuppressive medications and were analyzed in small retrospective studies. Both treatments yielded notable relief for patients; however, 38.5% (15/39) of patients receiving methotrexate experienced adverse events, and 50.0% (4/8) experienced adverse events with cyclosporine.^52,53

Thalidomide was studied in a small retrospective case review that showed notable improvement in PN. Dosages of thalidomide varied, but on average the dose was 100 mg/d. However, greater than 50% of patients experienced at least 1 adverse effect with this treatment.⁶³

A study performed in Italy showed promising results for patients treated with pregabalin, with 70.0% (21/30) continuing to take pregabalin for almost 2 years following completion of the initial 3-month trial.⁵⁵ Naltrexone decreased pruritus in more than half of patients (9/17).⁵⁹ Amitriptyline yielded improvements in patients with PN; however, disease recurred in 5 patients (29%) after 7 months.⁶² A study performed in Germany reported promising results for paroxetine and fluvoxamine; however, some patients enrolled in the study had some form of psychiatric disorder.⁶¹

Serlopitant, aprepitant, and nalbuphine were studied in randomized controlled trials. The serlopitant trials were the largest of the neurally mediated oral medication studies; one showed substantial improvement in patients with PN,⁵⁶ while the most recent trial did not show significant improvement (ClinicalTrials.gov identifier NCT03546816).⁵⁷ On the other hand, aprepitant showed no major difference between the experimental and placebo groups.⁵⁸ Nalbuphine 162 mg twice daily showed greater improvement in PN than nalbuphine 81 mg twice daily.⁶⁰

Immune-Mediated Injectable Therapies—Immune-targeted injectables include nemolizumab and dupilumab (Table 2). Nemolizumab is an IL-31 antagonist that has been studied in a small randomized controlled trial that showed great success in decreasing pruritus associated with PN.⁶⁴ IL-31 has been implicated in PN, and inhibition of the IL-31 receptor has been shown to disrupt the itch-scratch cycle of PN. Dupilumab is a monoclonal antibody against the IL-4 and IL-13 receptors, and it is the only FDA-approved treatment for PN.⁶⁵ Blockage of these protein receptors decreases type 2 inflammation and chronic pruritus.^66,67 Dupilumab is FDA approved for the treatment of atopic dermatitis and recently was approved for adults with PN. Dupilumab acts to block the shared α-subunit of the pruritogenic cytokines IL-4 and IL-13 pathways,²⁹ thereby breaking the itch-scratch cycle associated with PN and allowing for the healing of these lesions. Results from 2 clinical trials showed substantially reduced itch in patients with PN.⁶⁵ Dupilumab also was approved by the European Medicines Agency for moderate to severe PN.⁶⁸

Conclusion

Prurigo nodularis is a chronic condition that affects patient quality of life and can mimic various dermatologic conditions. The epidemiology and pathophysiology of PN have not been fully expounded. More research should be conducted to determine the underpinnings of PN to help identify more consistently effective therapies for this complex condition.

Prurigo nodularis (PN)(also called chronic nodular prurigo, prurigo nodularis of Hyde, or picker’s nodules) was first characterized by James Hyde in 1909.^1-3 Prurigo nodularis manifests with symmetrical, intensely pruritic, eroded, or hyperkeratotic nodules or papules on the extremities and trunk.^1,2,4,5 Studies have shown that individuals with PN experience pruritus, sleep loss, decreased social functioning from the appearance of the nodules, and a higher incidence of anxiety and depression, causing a negative impact on their quality of life.^2,6 In addition, the manifestation of PN has been linked to neurologic and psychiatric disorders; however, PN also can be idiopathic and manifest without underlying illnesses.^2,6,7

Prurigo nodularis has been associated with other dermatologic conditions such as atopic dermatitis (up to 50%), lichen planus, keratoacanthomas (KAs), and bullous pemphigoid.^7-9 It also has been linked to systemic diseases in 38% to 50% of cases, including chronic kidney disease, liver disease, type 2 diabetes mellitus, malignancies (hematopoietic, liver, and skin), and HIV infection.^6,8,10

The pathophysiology of PN is highly complex and has yet to be fully elucidated. It is thought to be due to dysregulation and interaction of the increase in neural and immunologic responses of proinflammatory and pruritogenic cytokines.^2,11 Treatments aim to break the itch-scratch cycle that perpetuates this disorder; however, this proves difficult, as PN is associated with a higher itch intensity than atopic dermatitis and psoriasis.¹⁰ Therefore, most patients attempt multiple forms of treatment for PN, ranging from topical therapies, oral immunosuppressants, and phototherapy to the newest and only medication approved by the US Food and Drug Administration for the treatment of PN—dupilumab.^1,7,11 Herein, we provide an updated review of PN with a focus on its epidemiology, histopathology and pathophysiology, comorbidities, clinical presentation, differential diagnosis, and current treatment options.

Epidemiology

There are few studies on the epidemiology of PN; however, middle-aged populations with underlying dermatologic or psychiatric disorders tend to be impacted most frequently.^2,12,13 In 2016, it was estimated that almost 88,000 individuals had PN in the United States, with the majority being female; however, this estimate only took into account those aged 18 to 64 years and utilized data from IBM MarketScan Commercial Claims and Encounters Database (IBM Watson Health) from October 2015 to December 2016.¹⁴ More recently, a retrospective database analysis estimated the prevalence of PN in the United States to be anywhere from 36.7 to 43.9 cases per 100,000 individuals. However, this retrospective review utilized the International Classification of Diseases, Tenth Revision code; PN has 2 codes associated with the diagnosis, and the coding accuracy is unknown.¹⁵ Sutaria et al¹⁶ looked at racial disparities in patients with PN utilizing data from TriNetX and found that patients who received a diagnosis of PN were more likely to be women, non-Hispanic, and Black compared with control patients. However, these estimates are restricted to the health care organizations within this database.

In 2018, Poland reported an annual prevalence of 6.52 cases per 100,000 individuals,¹⁷ while England reported a yearly prevalence of 3.27 cases per 100,000 individuals.¹⁸ Both countries reported most cases were female. However, these studies are not without limitations. Poland only uses the primary diagnosis code for medical billing to simplify clinical coding, thus underestimating the actual prevalence; furthermore, clinical codes more often than not are assigned by someone other than the diagnosing physician, leaving room for error.¹⁷ In addition, England’s PN estimate utilized diagnosis data from primary care and inpatient datasets, leaving out outpatient datasets in which patients with PN may have been referred and obtained the diagnosis, potentially underestimating the prevalence in this population.¹⁸

In contrast, Korea estimated the annual prevalence of PN to be 4.82 cases per 1000 dermatology outpatients, with the majority being men, based on results from a cross-sectional study among outpatients from the Catholic Medical Center. Although this is the largest health organization in Korea, the scope of this study is limited and lacks data from other medical centers in Korea.¹⁹

Histopathology and Pathophysiology

Almost all cells in the skin are involved in PN: keratinocytes, mast cells, dendritic cells, endothelial cells, lymphocytes, eosinophils, collagen fibers, and nerve fibers.^11,20 Classically, PN manifests as a dome-shaped lesion with hyperkeratosis, hypergranulosis, and psoriasiform epidermal hyperplasia with increased thickness of the papillary dermis consisting of coarse collagen with compact interstitial and circumvascular infiltration as well as increased lymphocytes and histocytes in the superficial dermis (Figure 1).²⁰ Hyperkeratosis is thought to be due to either the alteration of keratinocyte structures from scratching or keratinocyte abnormalities triggering PN.²¹ However, the increase in keratinocytes, which secrete nerve growth factor, allows for neuronal hyperplasia within the dermis.²² Nerve growth factor can stimulate keratinocyte proliferation²³ in addition to the upregulation of substance P (SP), a tachykinin that triggers vascular dilation and pruritus in the skin.²⁴ The density of SP nerve fibers in the dermis increases in PN, causing proinflammatory effects, upregulating the immune response to promote endothelial hyperplasia and increased vascularization.²⁵ The increase in these fibers may lead to pruritus associated with PN.^2,26

Many inflammatory cytokines and mediators also have been implicated in PN. Increased messenger RNA expression of IL-4, IL-17, IL-22, and IL-31 has been described in PN lesions.^3,27 Furthermore, studies also have reported increased helper T cell (T_H2) cytokines, including IL-4, IL-5, IL-10, and IL-13, in the dermis of PN lesions in patients without a history of atopy.^3,28 These pruritogenic cytokines in conjunction with the SP fibers may create an intractable itch for those with PN. The interaction and culmination of the neural and immune responses make PN a complex condition to treat with the multifactorial interaction of systems. 

Comorbidities

Prurigo nodularis has been associated with a wide array of comorbidities; however, the direction of the relationship between PN and these conditions makes it difficult to discern if PN is a primary or secondary condition.²⁹ Prurigo nodularis commonly has been connected to other inflammatory dermatoses, with a link to atopic dermatitis being the strongest.^5,29 However, PN also has been linked to other pruritic inflammatory cutaneous disorders, including psoriasis, cutaneous T-cell lymphoma, lichen planus, and dermatitis herpetiformis.^14,29

Huang et al¹⁴ found an increased likelihood of psychiatric illnesses in patients with PN, including eating disorders, nonsuicidal self-injury disorder, attention-deficit/hyperactivity disorder, schizophrenia, mood disorders, anxiety, and substance abuse disorders. Treatments directed at the neural aspect of PN have included selective serotonin reuptake inhibitors (SSRIs), which also are utilized to treat these mental health disorders.

Furthermore, systemic diseases also have been found to be associated with PN, including hypertension, type 2 diabetes mellitus, chronic kidney disease, heart failure, cerebrovascular disease, coronary heart disease, and chronic obstructive pulmonary disease.¹⁴ The relationship between PN and systemic conditions may be due to increased systemic inflammation and dysregulation of neural and metabolic functions implicated in these conditions from increased pruritic manifestations.^29,30 However, studies also have connected PN to infectious conditions such as HIV. One study found that patients with PN had 2.68 higher odds of infection with HIV compared to age- and sex-matched controls.¹⁴ It is unknown if these conditions contributed to the development of PN or PN contributed to the development of these disorders.

Clinical Presentations

Prurigo nodularis is a chronic inflammatory skin disease that typically manifests with multiple severely pruritic, dome-shaped, firm, hyperpigmented papulonodules with central scale or crust, often with erosion, due to chronic repetitive scratching and picking secondary to pruritic systemic or dermatologic diseases or psychological disorders (Figure 2).^1,2,4,5,8,31 Most often, diagnosis of PN is based on history and physical examination of the lesion; however, biopsies may be performed. These nodules commonly manifest with ulceration distributed symmetrically on extensor extremities in easy-to-reach places, sparing the mid back (called the butterfly sign).⁸ Lesions—either a few or hundreds—can range from a few millimeters to 2 to 3 cm.^8,32 The lesions differ in appearance depending on the pigment in the patient’s skin. In patients with darker skin tones, hyperpigmented or hypopigmented papulonodules are not uncommon, while those with fairer skin tones tend to present with erythema.³¹

Differential Diagnosis

Because of the variation in manifestation of PN, these lesions may resemble other cutaneous conditions. If the lesions are hyperkeratotic, they can mimic hypertrophic lichen planus, which mainfests with hyperkeratotic plaques or nodules on the lower extremities.^8,29 In addition, the histopathology of lichen planus resembles the appearance of PN, with epidermal hyperplasia, hypergranulosis, hyperkeratosis, and increased fibroblasts and capillaries.^8,29

Pemphigoid nodularis is a rare subtype of bullous pemphigoid that exhibits characteristics of PN with pruritic plaques and erosions.^8,29,33 The patient population for pemphigoid nodularis tends to be aged 50 to 60 years, and females are affected more frequently than males. However, pemphigoid nodularis may manifest with blistering and large plaques, which are not seen commonly with PN.²⁹ On histopathology, pemphigoid nodularis deposits IgG and C3 on the basement membrane and has subepidermal clefting, unlike PN.^7,29

Actinic prurigo manifests with pruritic papules or nodules post–UV exposure to unprotected skin.^8,29,33 This rare condition usually manifests with cheilitis and conjunctivitis. Unlike PN, which commonly affects elderly populations, actinic prurigo typically is found in young females.^8,29 Cytologic examination shows hyperkeratosis, spongiosis, and acanthosis of the epidermis with lymphocytic perivascular infiltration of the dermis.³⁴

Neurotic excoriations also tend to mimic PN with raised excoriated lesions; however, this disorder is due to neurotic picking of the skin without associated pruritus or true hyperkeratosis.^8,29,33 Histopathology shows epidermal crusting with inflammation of the upper dermis.³⁵

Infiltrative cutaneous squamous cell carcinoma (SCC) may imitate PN in appearance. It manifests as tender, ulcerated, scaly plaques or nodules. Histopathology shows cytologic atypia with an infiltrative architectural pattern and presence of collections of compact keratin and parakeratin (called keratin pearls).

Keratoacanthomas can resemble PN lesions. They usually manifest as nodules measuring 1 to 2 cm in diameter and 0.5 cm thick, resembling crateriform tumors.³⁶ On histopathology, KAs can resemble SCCs; however, KAs tend to manifest more frequently with a keratin-filled crater with a ground-glass appearance.³⁶

Inverted follicular keratosis commonly manifests on the face in elderly men as a single, flesh-colored, verrucous papule that may resemble PN. However, cytology of inverted follicular keratosis is characterized by proliferation and squamous eddies.³⁷ Consideration of the histologic findings and clinical appearance are important to differentiate between PN and cutaneous SCC.

Pseudoepitheliomatous hyperplasia is a benign condition that manifests as a plaque or nodule with crust, scale, or ulceration. Histologically, this condition presents with hyperplastic proliferation of the epidermis and adnexal epithelium.³⁸ The clinical and histologic appearance can mimic PN and other cutaneous eruptions with epidermal hyperplasia. 

In clinical cases that are resistant to treatment, biopsy is the best approach to diagnose the lesion. Due to similarities in physical appearance and superficial histologic presentation of PN, KAs from SCC, hypertrophic lichen planus, and other hyperkeratotic lesions, the biopsy should be taken at the base of the lesion to sample deeper layers of skin to differentiate these dermatologic disorders.

Management

Current treatments for PN yield varied results. Many patients with moderate to severe PN attempt multiple therapies before seeing improvement.³¹ Treatments include topical, oral, and injectable medications and are either directed at the neural or immune components of PN due to the interplay between increased nerve fibers in the lesions (neural axis) as well as increases in cytokines and other immunologic mediators (immune axis) of this condition. However, the FDA recently approved the first treatment for PN—dupilumab—which is an injectable IL-4 receptor antagonist directed at the immunologic interactions affiliated with PN.

Immune-Mediated Topical Therapies—Immunologic topical therapies include corticosteroids, calcipotriol, and calcineurin inhibitors. Studies that have analyzed these treatments are limited to case reports and small intraindividual and randomized controlled trials (Table 1). Topical therapies usually are first-line agents for most patients. Adverse effects include transient irritation of the skin.^40,42,43

Supplements—N-acetyl cysteine is an over-the-counter supplement that has been reported to improve symptoms in patients with skin-picking disorders.⁴⁸ The mechanism of action includes antioxidant effects such as decreasing reactive oxygen species, decreasing inflammatory markers, regulating neurotransmitters, and inhibiting hyperkeratosis.⁴⁹ N-acetyl cysteine has been poorly studied for its application in PN. A small study of 3 patients with subacute PN receiving 1200 mg of oral N-acetyl cysteine reported varying levels of improvement in skin appearance and reduction in skin picking.⁵⁰

Phototherapy—Phototherapy, a typical first- or second-line treatment modality for PN, targets both the neural- and immune-mediated aspects associated with pruritus in PN (Table 1).⁵¹ UV light can penetrate through the epidermal layer of the skin and reach the keratinocytes, which play a role in the immune-related response of PN. In addition, the cutaneous sensory nerves are located in the upper dermal layer, from which nerve fibers grow and penetrate into the epidermis, thereby interacting with the keratinocytes where pruritic signals are transmitted from the periphery up to the brain.⁵¹

Studies analyzing the effects of phototherapy on PN are limited to case series and a small randomized controlled trial. However, this trial has shown improvements in pruritus in the participants. Adverse effects include transient burning and erythema at the treated sites.^44,45

Immune-Mediated Oral Therapies—Immunologic-targeted oral therapies include bilastine, methotrexate, and cyclosporine (Table 2).^52,53 Bilastine efficacy was analyzed in a small phase 3, open-label, multicenter study in Japan; however, patients were allowed to use topical steroids in conjunction with the oral antihistamine.⁵⁴ Methotrexate and cyclosporine are immunosuppressive medications and were analyzed in small retrospective studies. Both treatments yielded notable relief for patients; however, 38.5% (15/39) of patients receiving methotrexate experienced adverse events, and 50.0% (4/8) experienced adverse events with cyclosporine.^52,53

Thalidomide was studied in a small retrospective case review that showed notable improvement in PN. Dosages of thalidomide varied, but on average the dose was 100 mg/d. However, greater than 50% of patients experienced at least 1 adverse effect with this treatment.⁶³

A study performed in Italy showed promising results for patients treated with pregabalin, with 70.0% (21/30) continuing to take pregabalin for almost 2 years following completion of the initial 3-month trial.⁵⁵ Naltrexone decreased pruritus in more than half of patients (9/17).⁵⁹ Amitriptyline yielded improvements in patients with PN; however, disease recurred in 5 patients (29%) after 7 months.⁶² A study performed in Germany reported promising results for paroxetine and fluvoxamine; however, some patients enrolled in the study had some form of psychiatric disorder.⁶¹

Serlopitant, aprepitant, and nalbuphine were studied in randomized controlled trials. The serlopitant trials were the largest of the neurally mediated oral medication studies; one showed substantial improvement in patients with PN,⁵⁶ while the most recent trial did not show significant improvement (ClinicalTrials.gov identifier NCT03546816).⁵⁷ On the other hand, aprepitant showed no major difference between the experimental and placebo groups.⁵⁸ Nalbuphine 162 mg twice daily showed greater improvement in PN than nalbuphine 81 mg twice daily.⁶⁰

Immune-Mediated Injectable Therapies—Immune-targeted injectables include nemolizumab and dupilumab (Table 2). Nemolizumab is an IL-31 antagonist that has been studied in a small randomized controlled trial that showed great success in decreasing pruritus associated with PN.⁶⁴ IL-31 has been implicated in PN, and inhibition of the IL-31 receptor has been shown to disrupt the itch-scratch cycle of PN. Dupilumab is a monoclonal antibody against the IL-4 and IL-13 receptors, and it is the only FDA-approved treatment for PN.⁶⁵ Blockage of these protein receptors decreases type 2 inflammation and chronic pruritus.^66,67 Dupilumab is FDA approved for the treatment of atopic dermatitis and recently was approved for adults with PN. Dupilumab acts to block the shared α-subunit of the pruritogenic cytokines IL-4 and IL-13 pathways,²⁹ thereby breaking the itch-scratch cycle associated with PN and allowing for the healing of these lesions. Results from 2 clinical trials showed substantially reduced itch in patients with PN.⁶⁵ Dupilumab also was approved by the European Medicines Agency for moderate to severe PN.⁶⁸

Conclusion

Prurigo nodularis is a chronic condition that affects patient quality of life and can mimic various dermatologic conditions. The epidemiology and pathophysiology of PN have not been fully expounded. More research should be conducted to determine the underpinnings of PN to help identify more consistently effective therapies for this complex condition.

To the Editor:

Pityriasis rubra pilaris (PRP) is a rare papulosquamous condition with an unknown pathogenesis and limited efficacy data, which can make treatment challenging. Some cases of PRP spontaneously resolve in a few months, which is most common in the pediatric population.¹ Pityriasis rubra pilaris in adults is likely to persist for years, and spontaneous resolution is unpredictable. Randomized clinical trials are difficult to perform due to the rarity of PRP.

Although there is no cure and no standard protocol for treating PRP, systemic retinoids historically are considered first-line therapy for moderate to severe cases.² Additional management approaches include symptomatic control with moisturizers and psychological support. Alternative systemic treatments for moderate to severe cases include methotrexate, phototherapy, and cyclosporine.²

Pityriasis rubra pilaris demonstrates a favorable response to methotrexate treatment, especially in type I cases; however, patients on this alternative therapy should be monitored for severe adverse effects (eg, hepatotoxicity, pancytopenia, pneumonitis).² Phototherapy should be approached with caution. Narrowband UVB, UVA1, and psoralen plus UVA therapy have successfully treated PRP; however, the response is variable. In some cases, the opposite effect can occur, in which the condition is photoaggravated. Phototherapy is a valid alternative form of treatment when used in combination with acitretin, and a phototest should be performed prior to starting this regimen. Cyclosporine is another immunosuppressant that can be considered for PRP treatment, though there are limited data demonstrating its efficacy.²

The introduction of biologic agents has changed the treatment approach for many dermatologic diseases, including PRP. Given the similar features between psoriasis and PRP, the biologics prescribed for psoriasis therapy also are used for patients with PRP that is challenging to treat, such as anti–tumor necrosis factor α inhibitors and IL inhibitors—specifically IL-17 and IL-23. Remission has been achieved with the use of biologics in combination with retinoid therapy.²

Biologic therapies used for PRP effectively inhibit cytokines and reduce the overall inflammatory processes involved in the development of the scaly patches and plaques seen in this condition. However, most reported clinical experiences are case studies, and more research in the form of randomized clinical trials is needed to understand the efficacy and long-term effects of this form of treatment in PRP. We present a case of a patient with refractory adult subtype I PRP that was successfully treated with the IL-23 inhibitor risankizumab.

A 65-year-old man was referred to Florida Academic Dermatology Center (Coral Gables, Florida) with biopsy-proven PRP diagnosed 1 year prior. The patient reported experiencing a debilitating quality of life in the year since diagnosis (Figure 1). Treatment attempts with dupilumab, tralokinumab, intramuscular steroid injections, and topical corticosteroids had failed (Figure 2). Following evaluation at Florida Academic Dermatology Center, the patient was started on acitretin 25 mg every other day and received an initial subcutaneous injection of ixekizumab 160 mg (an IL-17 inhibitor) followed 2 weeks later by a second injection of 80 mg. After the 2 doses of ixekizumab, the patient’s condition worsened with the development of pinpoint hemorrhagic lesions. The medication was discontinued, and he was started on risankizumab 150 mg at the approved dosing regimen for plaque psoriasis in combination with the acitretin therapy. Prior to starting risankizumab, the affected body surface area (BSA) was 80%. At 1-month follow-up, he showed improvement with reduction in scaling and erythema and an affected BSA of 30% (Figure 3). At 4-month follow-up, he continued showing improvement with an affected BSA of 10% (Figure 4). Acitretin was discontinued, and the patient has been successfully maintained on risankizumab 150 mg/mL subcutaneous injections every 12 weeks since.

To the Editor:

Pityriasis rubra pilaris (PRP) is a rare papulosquamous condition with an unknown pathogenesis and limited efficacy data, which can make treatment challenging. Some cases of PRP spontaneously resolve in a few months, which is most common in the pediatric population.¹ Pityriasis rubra pilaris in adults is likely to persist for years, and spontaneous resolution is unpredictable. Randomized clinical trials are difficult to perform due to the rarity of PRP.

Although there is no cure and no standard protocol for treating PRP, systemic retinoids historically are considered first-line therapy for moderate to severe cases.² Additional management approaches include symptomatic control with moisturizers and psychological support. Alternative systemic treatments for moderate to severe cases include methotrexate, phototherapy, and cyclosporine.²

Pityriasis rubra pilaris demonstrates a favorable response to methotrexate treatment, especially in type I cases; however, patients on this alternative therapy should be monitored for severe adverse effects (eg, hepatotoxicity, pancytopenia, pneumonitis).² Phototherapy should be approached with caution. Narrowband UVB, UVA1, and psoralen plus UVA therapy have successfully treated PRP; however, the response is variable. In some cases, the opposite effect can occur, in which the condition is photoaggravated. Phototherapy is a valid alternative form of treatment when used in combination with acitretin, and a phototest should be performed prior to starting this regimen. Cyclosporine is another immunosuppressant that can be considered for PRP treatment, though there are limited data demonstrating its efficacy.²

The introduction of biologic agents has changed the treatment approach for many dermatologic diseases, including PRP. Given the similar features between psoriasis and PRP, the biologics prescribed for psoriasis therapy also are used for patients with PRP that is challenging to treat, such as anti–tumor necrosis factor α inhibitors and IL inhibitors—specifically IL-17 and IL-23. Remission has been achieved with the use of biologics in combination with retinoid therapy.²

Biologic therapies used for PRP effectively inhibit cytokines and reduce the overall inflammatory processes involved in the development of the scaly patches and plaques seen in this condition. However, most reported clinical experiences are case studies, and more research in the form of randomized clinical trials is needed to understand the efficacy and long-term effects of this form of treatment in PRP. We present a case of a patient with refractory adult subtype I PRP that was successfully treated with the IL-23 inhibitor risankizumab.

A 65-year-old man was referred to Florida Academic Dermatology Center (Coral Gables, Florida) with biopsy-proven PRP diagnosed 1 year prior. The patient reported experiencing a debilitating quality of life in the year since diagnosis (Figure 1). Treatment attempts with dupilumab, tralokinumab, intramuscular steroid injections, and topical corticosteroids had failed (Figure 2). Following evaluation at Florida Academic Dermatology Center, the patient was started on acitretin 25 mg every other day and received an initial subcutaneous injection of ixekizumab 160 mg (an IL-17 inhibitor) followed 2 weeks later by a second injection of 80 mg. After the 2 doses of ixekizumab, the patient’s condition worsened with the development of pinpoint hemorrhagic lesions. The medication was discontinued, and he was started on risankizumab 150 mg at the approved dosing regimen for plaque psoriasis in combination with the acitretin therapy. Prior to starting risankizumab, the affected body surface area (BSA) was 80%. At 1-month follow-up, he showed improvement with reduction in scaling and erythema and an affected BSA of 30% (Figure 3). At 4-month follow-up, he continued showing improvement with an affected BSA of 10% (Figure 4). Acitretin was discontinued, and the patient has been successfully maintained on risankizumab 150 mg/mL subcutaneous injections every 12 weeks since.

To the Editor:

Pityriasis rubra pilaris (PRP) is a rare papulosquamous condition with an unknown pathogenesis and limited efficacy data, which can make treatment challenging. Some cases of PRP spontaneously resolve in a few months, which is most common in the pediatric population.¹ Pityriasis rubra pilaris in adults is likely to persist for years, and spontaneous resolution is unpredictable. Randomized clinical trials are difficult to perform due to the rarity of PRP.

Although there is no cure and no standard protocol for treating PRP, systemic retinoids historically are considered first-line therapy for moderate to severe cases.² Additional management approaches include symptomatic control with moisturizers and psychological support. Alternative systemic treatments for moderate to severe cases include methotrexate, phototherapy, and cyclosporine.²

Pityriasis rubra pilaris demonstrates a favorable response to methotrexate treatment, especially in type I cases; however, patients on this alternative therapy should be monitored for severe adverse effects (eg, hepatotoxicity, pancytopenia, pneumonitis).² Phototherapy should be approached with caution. Narrowband UVB, UVA1, and psoralen plus UVA therapy have successfully treated PRP; however, the response is variable. In some cases, the opposite effect can occur, in which the condition is photoaggravated. Phototherapy is a valid alternative form of treatment when used in combination with acitretin, and a phototest should be performed prior to starting this regimen. Cyclosporine is another immunosuppressant that can be considered for PRP treatment, though there are limited data demonstrating its efficacy.²

The introduction of biologic agents has changed the treatment approach for many dermatologic diseases, including PRP. Given the similar features between psoriasis and PRP, the biologics prescribed for psoriasis therapy also are used for patients with PRP that is challenging to treat, such as anti–tumor necrosis factor α inhibitors and IL inhibitors—specifically IL-17 and IL-23. Remission has been achieved with the use of biologics in combination with retinoid therapy.²

Biologic therapies used for PRP effectively inhibit cytokines and reduce the overall inflammatory processes involved in the development of the scaly patches and plaques seen in this condition. However, most reported clinical experiences are case studies, and more research in the form of randomized clinical trials is needed to understand the efficacy and long-term effects of this form of treatment in PRP. We present a case of a patient with refractory adult subtype I PRP that was successfully treated with the IL-23 inhibitor risankizumab.

A 65-year-old man was referred to Florida Academic Dermatology Center (Coral Gables, Florida) with biopsy-proven PRP diagnosed 1 year prior. The patient reported experiencing a debilitating quality of life in the year since diagnosis (Figure 1). Treatment attempts with dupilumab, tralokinumab, intramuscular steroid injections, and topical corticosteroids had failed (Figure 2). Following evaluation at Florida Academic Dermatology Center, the patient was started on acitretin 25 mg every other day and received an initial subcutaneous injection of ixekizumab 160 mg (an IL-17 inhibitor) followed 2 weeks later by a second injection of 80 mg. After the 2 doses of ixekizumab, the patient’s condition worsened with the development of pinpoint hemorrhagic lesions. The medication was discontinued, and he was started on risankizumab 150 mg at the approved dosing regimen for plaque psoriasis in combination with the acitretin therapy. Prior to starting risankizumab, the affected body surface area (BSA) was 80%. At 1-month follow-up, he showed improvement with reduction in scaling and erythema and an affected BSA of 30% (Figure 3). At 4-month follow-up, he continued showing improvement with an affected BSA of 10% (Figure 4). Acitretin was discontinued, and the patient has been successfully maintained on risankizumab 150 mg/mL subcutaneous injections every 12 weeks since.