Prurigo Nodularis: a Benign Dermatosis Derived from a Persistent Pruritus
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Acta Dermatovenerol Croat 2008;16(1): Acta Dermatovenerol Croat 2008;16(1):38-44 REVIEW Prurigo Nodularis: A Benign Dermatosis Derived from a Persistent Pruritus Darshan C. Vaidya, Robert A. Schwartz Dermatology & Pathology, New Jersey Medical School, Newark, New Jersey, USA Corresponding author: SUMMARY Prurigo nodularis (PN) is a benign neurodermatitis of Prof. Robert A. Schwartz, MD, MPH unknown etiology characterized by firm, hyperkeratotic pruritic nodules most commonly localized symmetrically on the bilateral extensor Professor and Head, Dermatology lower extremities. PN represents a primary dermatological condition New Jersey Medical School or a dermatological manifestation of repeated traumatic manipulation 185 South Orange Avenue secondary to chronic pruritus. One must consider underlying causes of Newark, New Jersey 07103 pruritus, which may include psychiatric disorders and internal disease. Given its chronicity and relapsing nature, treatment of PN can be U.S.A. challenging. Interruption of the itch-scratch cycle is difficult; long term [email protected] prognosis remains guarded. KEY WORDS: prurigo nodularis, neurodermatitis, neurohyperplasia, Received: November 29, 2007 lichen simplex chronicus, atopic dermatitis, HIV disease Accepted: January 15, 2008 INTRODUCTION Prurigo nodularis (PN), first described by Hard- Recent advances have been made in treatment; away in 1880 and named by Hyde and Montgom- however, much remains to be done. ery (1) in 1909, is a chronic, benign neurodermati- Many conditions may trigger PN, such as arthro- tis of unclear etiology characterized by excoriated, pod bite reactions, psychiatric illness, and systemic intensely pruritic nodules, which are secondary disease, including internal malignancy (Table 2); to an intense itch-scratch cycle. It is found mostly however, a direct causal link has yet to be found. It on exposed extensor skin surfaces of the lower has been postulated that nerve growth factor (NGF), extremities. After vigorous scratching or rubbing, substance P, and various other neuropeptides as cutaneous manifestations may include lichenifica- well as mast cells and eosinophils are involved in tion, neurotic excoriations and ultimately nodula- the inflammatory and pruritic response of skin in PN tion, PN. Postinflammatory hypopigmentation or (3). The mainstay of treatment for intense pruritus hyperpigmentation can also result, often central should initially be to detect and subsequently treat hypopigmentation highlighted by border hyperpig- any underlying cause. However, this daunting task mentation. Recently, the International Forum for is usually unaccomplished, and symptomatic relief the Study of Itch proposed a classification of the remains the only option. Unfortunately, chronic pru- various diseases that present with itch as a means ritus in general and prurigo nodularis specifically of facilitating diagnosis and improving treatment are difficult to treat. Topical and intralesional cor- modalities and outcomes. PN falls under group III, ticosteroids, calcipotriol, capsaicin, narrow-band which encompasses chronic secondary scratch UVB, thalidomide, and cyclosporine (4) have been lesions (2). There are three types of PN (Table 1). used with only limited success. 38 Vaidya and Schwartz Acta Dermatovenerol Croat Prurigo nodularis 2008;16(1):38-44 Table 1. Forms of prurigo Table 2. Conditions associated with prurigo nodu- - Atopic prurigo nodularis laris - HIV-associated prurigo nodularis - Arthropod bite reactions - Non-atopic non-HIV linked prurigo nodularis - Venous stasis - Folliculitis - Psychosomatic disorders EPIDEMIOLOGY - Depression - Anxiety As initially described by Hyde and Montgomery - Hyperthyroidism (1), PN most commonly affects the middle-aged - Iron deficiency anemia and elderly, although it has been seen in young - Chronic renal failure men and children as well (5). Classically, two - Chronic liver disease (hepatitis B and C, α-1 forms of PN are often delineated: atopic PN and antitrypsin deficiency, primary biliary cirrhosis, non-atopic PN (6). Atopic PN has an earlier onset primary sclerosing cholangitis, other cirrhotic and seems to be associated with atopic dermatitis, conditions) - Human immunodeficiency virus while simultaneously displaying hypersensitivity to - Manifestation of underlying renal/hepatic/ various environmental allergens. Non-atopic PN, gastrointestinal disease or malignancy in contrast, has an older age of onset and lacks - Mycobacterial infection a cutaneous response to allergens. Among our - Leukemia patients, we have distinguished a third form that - Lymphoma is associated with human immunodeficiency virus (HIV) disease (Table 1). PN in some patients, especially those classified as PN may be viewed as a hyperplastic form of li- compulsive “pickers” (12). Depression and anxiety chen simplex chronicus (6). There is no racial or maintain a close association (13). In patients with sexual predilection for PN, and no increase in mor- chronic kidney disease, imbalances in levels and tality other than that associated with the underlying accumulation of calcium, phosphorus, magnesium, cause (7). Importantly, psychosocial morbidity of and aluminum, especially in hemodialysis patients, chronic, unrelenting, intense pruritus may be sig- can be a significant cause of pruritus (3). Viral in- nificantly damaging to one’s quality of life (8). fection with subsequent immune complex depo- sition in the skin has also been implicated in PN HistoPathoLOGY pathogenesis, most commonly with chronic hepati- tis B (14), hepatitis C (15) and HIV (16) infections. Microscopically, a typical PN nodule may show hypertrophy of cutaneous nerves in the dermis Mast cells, eosinophils, neutrophils, and various (9,10). It has further been demonstrated that der- component proteins and substances have been mal nerves display an inclination towards neuro- studied to ascertain their role in the pathogenesis nal hyperplasia (11). Interestingly, PN also shares of PN. Mast cells not only increase in number, but some features with both psoriasis and ichthyosis also show changes in morphology, such as an en- as it demonstrates parakeratotoic hyperkeratosis larged cell body and a more dendritic shape com- accompanied by acanthosis and papillomatosis. pared to that in normal skin (17). There is no sig- Rete ridge elongation with a dense dermal lym- nificant increase in the concentration of mast cell phohistiocytic infiltrate may also be evident (7). tryptase or neutrophil elastase in the surrounding Epidermal changes are most typical while neu- tissue (10). A key culprit detected in diagnostic ronal changes are neither commonly evident nor skin biopsies of PN is the increased concentra- required for diagnosis. Using electron microscopy, tion of eosinophil degranulation products, such as one can see nerve fibers thickened and dilated eosinophil granule major basic protein, eosinophil with hyperproliferation of Schwann cells and ax- cationic protein, and eosinophil-derived neurotox- ons along with vacuolization and degeneration of in, which all have potent ability to damage nerves Schwann cells including disruption of internal or- and exacerbate inflammation (10,17). Interesting- ganelle architecture (10). ly, increased circulating and infiltrating eosinophils in conjunction with their component proteins are also implicated in symptomatic atopic dermatitis ETIOLOGY AND PathoGENESIS (18). PN has generated many theories as to its Mast cells have also been implicated in the pathogenesis. Emotional stress may contribute to pathogenesis of PN through a NGF: nerve growth ACTA DERMATOVENEROLOGICA CROATICA 39 Vaidya and Schwartz Acta Dermatovenerol Croat Prurigo nodularis 2008;16(1):38-44 Figure 1. Multiple, excoriated, hyperkeratotic nod- ules with areas of post-inflammatory hyperpig- Solitary hyperkeratotic nodule (bottom) mentation. Figure 2. and hyperkeratotic plaque (top) with adjacent li- factor receptor (NGFr) mechanism. Mast cells are chenification. known to release NGF. With increased mast cells nation are crucial. Underlying causes may include in PN, there is enhanced NGF expression, which significant internal pathology such as liver or kid- may produce neurohyperplasia (19). In normal ney disease, leukemia, lymphoma, or other ma- skin, there is weak immunoreactive epidermal and lignancy (Table 2). Physical examination should dermal staining for NGF and p75 NGFr. In con- carefully assess for jaundice and other signs of trast, both are overexpressed in Schwann cells liver disease, hyper- or hypothyroidism, lymph- and perineurium cells in hyperplastic PN nerves, adenopathy, infectious etiologies, xerosis, or other facilitating the neurohyperplasia seen in this dis- abnormalities of the hair, nails, or mucous mem- ease (20,21). branes. Nodular scabies should be considered Other skin findings thought to be involved in the (24). Neurodermatitis without prurigo nodules may pathogenesis of PN include an increase in both represent dermatitis herpetiformis, pemphigus epidermal Merkel cells (22) and dermal Langer- nodularis, and linear IgA bullous dermatitis. hans cells (23). PN is characterized by several to hundreds of hyperkeratotic, excoriated, pruritic papules or CLINICAL Features AND nodules with a tendency for symmetric distribution over the extensor surfaces of extremities. They SIGNIFICANCE can vary in size from 2-3 mm to 2 cm in diam- Pruritic processes may be first evident in a eter, appearing well demarcated, firm, scaly, and manner consistent with either a primary