Sector of Dermatology and the Post Graduation Course of Dermatology, School of Medicine, HUCFF-UFRJ, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Prurigo nodularis of Hyde is an unusual disorder of unknown etiology characterized by extremely pruritic nodules, although clinical and histopathological aspects are well defined. Literature on this disease is reviewed, focusing its historical background, etiology, pathogenesis, histopathology and ultrastructure, clinical aspects, differential diagnosis and therapeutic alternatives.
Key-words: Prurigo nodularis; prurigo; thalidomide.
In 1909, Hyde described a rare and untreatable idiopathic eruption, characterized by numerous persistent nodules affecting mainly the extensor surface of arms and legs of women that he called prurigo nodularis (PN).1 Cases mentioned previously by Hardaway, in 1880, as "multiple skin tumors accompanied by intense pruritus"2 and Brocq, in 1900, as "lichen obtusus corneus"3 are accepted as being the same entity. Pautrier, in 1934, using the Masson stain demonstrated the presence of neural dermal hyperplasia (Pautrier's neuroma) which he considered pathognomonic of the disease.4 In 1949, Pérez and Maruri5 studied deeper the neural alterations in the dermis; and Crown,6 in 1964, described the formation of schwannomas. Later, in 1975, Feuerman & Sandbank7 observed peculiarities under the electron microscope. Doyle et al.,8 in 1979, and Payne et al.,9 in 1985, did not find great neuroma formation in PN lesions in their series.
PN is a relatively rare, distinctive affection with an eminently clinical diagnosis.10 It is a chronic entity, occurring in adults, especially middle-aged women.10 Cases affecting children have also been described.11,12 Lesions are hard nodules, round and keratotic, and may present a depressed surface. Lichenoid plaques are also a frequent finding. Intense excoriation and post-inflammatory hyperpigmentation may be present. The number of lesions may vary from a few to hundreds. There is a tendency for symmetrical distribution, with predominance of the extensor surface of limbs.10 Payne et al.9 observed that the sacral region was affected in 50% and the abdominal region in 44% of their patients; while the face, palms and soles were little affected.
The skin between the nodules is, in general, normal, but may also be xerodermic and lichenified.9,10 Hirschel-Scholz et. al.13 advised about the possibility of the PN lesions to show regression leaving areas of anetoderma.
and morbid associations
PN is a papulonodular, pruriginous eruption of unknown cause, although it has been suggested that its etiopathogeny is related to neuronal, traumatic and metabolic factors.9,10
It is not known what happens first in PN patients, if pruritus or excoriation.10 Proliferation of peripheral nerves has been suggested to be caused by mechanical trauma.14 Wollina et al.15 observed that the arrangement of the papules followed preferably the skin cleavage lines, but not the Blaschko lines. This supports the inclusion of PN in the group of chronic traumatic papulosis.
For Weyers,16 PN, lichen simplex chronicus (LSC) and lichen amyloidosus would belong to the same kind of disease spectrum, due to the presence of pruritus, excoriations and similar histopathologic characteristics.
PN is considered by many authors as an atypical nodular form of circumscribed neurodermatitis.17 However, Vaalasti et al.,18 observing indirect immunofluorescence, noted that nervous bundles obtained from PN lesions showed increased immunoreactivity to the substance P and the calcitonine gene-related protein (CGRP). These findings were not observed in specimens obtained from patients with circumscribed neurodermatitis, when compared with the normal skin. Similar findings were later reported by other authors.19 It is believed that these neuropeptides are possible mediators of the neurogenic inflammation and allergic and inflammatory skin reactions. They are powerful histamine liberation agents, being possibly responsible for the severe pruritus of PN lesions, either directly or indirectly.
Harris et al.20 found an increase in the number of nerves in the papilar dermis in 24 out of 25 patients with PN, through immunohistochemical determination for S-100 protein. On the other hand, cutaneous nerves were demonstrated in only one of 25 patients with epidermal hyperplasia with pruritus (LSC) and in no patient with epidermal hyperplasia without pruritus. The authors concluded that the hypertrophy of dermal nerves is a quite constant finding in PN and its presence suggests a pathogenic neurocutaneous component.
Nahass & Penneys21 demonstrated, through the immunohistochemical technique with specific primary antibody for cytokeratin of low molecular weight (CK 8 - clone CAM 5,2), that the Merkel cells are increased in number in PN and may be a component of the neurocutaneous abnormality associated with this disorder. In general, these cells are found either isolated in the epidermis or associated with epithelial nerve endings, and represent slowly adapting sensory touch receptors. These authors did not observe similar alterations in LSC specimens.
Perez at al.22 studied the location of mastocytic tryptase, neutrophilic elastase, eosinophil granule major basic protein, eosinophilic cationic protein and eosinophil-derived neurotoxin, in affected skin of PN patients, through the technique of indirect immunofluorescence. They found an increase in the number of mast cells and in the eosinophil degranulation, evidenced by the significant extracellular deposits of granular proteins. In contrast, there was no extracellular deposition of mast cell and neutrophilic proteins. As it seems that proteins from the eosinophil granules may cause powerful effects on tissues, these authors suggest that the toxicity of these proteins and their deposition on affected tissue reveals a pathogenic role of the eosinophil in this disorder. In fact, a previous study demonstrated high serum levels of eosinophilic cationic protein (ECP) in patients with PN, although in some cases the number of circulating eosinophils was found to be normal.23 An increased number of activated eosinophils, demonstrated by immuno-labeling with EG-2 antibody which recognizes the eosinophilic protein X and ECP, were found in the affected skin.
In 1992, Geary & Cooper24 studied, through the immunoperoxidase technique, the distribution of the nuclear antigen of the proliferating cell (PCNA) in common epidermal lesions, in order to identify and specify proliferating cell populations. In the 11 cases of PN studied they noted an ordered pattern of antigen expression where the moderately and strongly positive cell nuclei were distributed in a continuous layer, basal-suprabasal, of relatively uniform thickness. There was a gradual loss and, finally, abolition of the antigen staining in progressively more superficial epidermal cells. This pattern was better developed in the central areas of the lesions and decreased gradually in direction of the specimen margins, being compatible with hyperplasia in response to an exogenous stimulus, as occurs in PN, with the more proliferative areas corresponding to places nearer to the stimulation.
Loricrin, the major component of the horny envelope, is normally expressed in the granular layer of the epidermis during the last steps of the keratinocyte differentiation. Its presence was not found in the affected skin of PN patients, indicating an incomplete differentiation of the affected area.25
An association between PN and several pruriginous states have been observed. Miyachi et al.26 noted an increase incidence of atopy (defined as personal or family history of atopic dermatitis, asthma or allergic rhinitis) in patients with PN, when compared to the general population. The authors suggested that atopic individuals, being more sensible to the "triggers" which cause excoriations, are prone to PN. Therefore, an increased predominance to PN in any subjacent pruriginous state would be expected. Tanaka et al.27 demonstrated, through an immunoallergic study, two types of PN, one atopic and the other non-atopic. The patients of the first group were younger and displayed patterns of hypersensitivity to environmental allergens similar to those verified in those with atopic dermatitis, while the other group consisted of older patients who did not present reactions to the majority of these allergens.
Shaffer & Beerman28 and Payne et al.9 noted that the eczematoid spectrum might be seen in certain PN patients. Zelickson et al.29 described three patients with positive patch tests, who improved from the PN lesions simply by avoiding allergens.
Deficiency of alfa-1-antitripsin was observed in a patient with disseminated PN. A deficiency of this major antiproteinase, a neutralizer of multiple proteolytic enzymes (elastase, collagenase, tripsin, chemotripsin, etc.) results in a significant tissue autodigestion. The authors reported a patient with this deficiency who, after insect bites and cellulitis, developed generalized pruritus and excoriations, evolving into disseminated PN lesions. Colonization of multiple skin lesions with Staphylococcus aureus and the liberation of powerful mitogens of T-cells, such as protein A and enterotoxin A of the bacterial cellular membrane, may result in additional liberation of proteolytic enzymes by activated lymphocytes and macrophages, without the concurrent secretion of alfa-1-antitripsin and subsequent aggravation of the pruritus. These concepts are based on the evidence by excessive tissue autodigestion revealed by electron microscopy, and by immunocytochemical information identifying the presence of T helper and T cytotoxic/suppressor lymphocytes, as well as macrophages in the upper dermis.30
Mattila et al.31 studied 43 PN patients, from the histopathologic and microbiologic standpoint, besides testing them for intracutaneous reactivity to 12 mycobacterial antigens (Mantoux technique). In six specimens (14%) there was mycobacteria growth in culture. In histopathology, 12 samples (28%) were positive for alcohol-acid resistant bacilli and granulomatous alterations were present in one of them. Patients with positive cultures to mycobacteria had more intense intradermal reactions to mycobacterial antigens. Two patients accepted to submit to two years of tuberculostatic chemotherapy, one obtaining excellent response and the other partial results. The authors suggested that the detection of mycobacteria, through cultures or special tissue staining combined with elevated cutaneous reactivity to these microorganisms, in a great proportion of patients with PN might indicate a mycobacterial cause.
Boer & Smeenk32
described two cases of lesions similar to PN, with patients using etretinate
for treatment of hyperkeratotic eczema of palms and soles. In one of them, a
defined reaction between the drug and the cutaneous eruption was proven by the
effect of reintroducing the drug.
Payne et al.,9 in a study of 46 PN cases, found that 50% presented potential metabolic causes of pruritus, such as anemia, hepatic dysfunction, uremia and myxedema. Focal causes of pruritus were important in 37% and included insect bites, venous stasis, folliculitis and nummular eczema. Similar associations were also observed by others.33,34
Brown et al.35 described a case of PN and aluminum overload associated to maintenance hemodialysis. The pruritus and lesions disappeared after treatment with an aluminum chelating agent, desferrioxamine.
The association between PN and enteropathy by gluten in a same patient is more than a fortuitous event. This relation was first described by Wells,36 and new cases were described by Howell,37 McKenzie et al.,38 Goodwin39 and Suárez et al..40 With the introduction of a gluten-free diet, a clinical improvement of the intestinal and cutaneous symptoms was reported in all cases.
Although pruritus is the most common dermatologic symptom in Hodgkin's disease patients (HD), an association with PN has been reported occasionally. In 1917, Cole41 reviewed 33 cases of HD and found generalized pruritus in eight and prurigo-like eruptions in six cases. In 1925, Shilmire42 had observed one-hundred cases of prurigo-like eruptions accompanied by HD. Schelnitz & Paller,11 in 1990, reported a case of an adolescent with PN with a HD presentation sign (stage II), primarily in the mediastinum; and the pruritus and associated skin lesions were cured with combined chemotherapy. In the following year, Fina et al.43 described a similar picture in a 22-year-old girl.
Other lymphomas, leukemias, polycythemia vera, solid tumors and carcinoid syndrome may also be systemic causes of pruritus and should be excluded in patients with PN.10,44,45
Pruritus and excoriation are frequent complications in AIDS patients. In fact, among several cutaneous manifestations in HIV positive patients, PN was observed in 6.5% and 1.8% of patients in two studies, respectively. Isolated case reports have also been published.48,49
There is an observation of PN and bullous pemphigoid in the same patient, but the mechanisms through which the two entities are associated are unknown.50,51 Psychiatric factors contributing to the disease may be seen in chronic prurigo patients, but it is impossible to establish definite conclusions in the absence of consistent data.
and electron microscopy
The histology of PN lesions is characterized by hyperkeratosis and acanthosis. There may be additionally, papillomatosis and irregular proliferation of the epidermis to deeper layers, similar to pseudocarcinomatous hyperplasia. Classically, the alterations are focal, and its histologic appearance may be similar to chronic eczema or, with less frequency, to persistent reactions to insect bites.9,52
The dermis shows a non-specific inflammatory infiltrate, comprising histiocytes, lymphocytes, some mast cells and eosinophils. There is proliferation of fibroblasts and it is possible to find deposition of fibrin in a subepidermal localization.10,52,53
Pautrier4 observed the destruction of elastic fibers in his patients, and it is believed that this fact is a consequence of the production of elastolytic enzymes by the cells of the dermal inflammatory infiltrate.13
Ever since Pautrier4 described the "colossal hyperplasia of the nervous tissue", later called "Pautrier's neuroma", neural alterations in PN lesions have been object of investigation by optical and electron microscopy. Several authors concluded that in PN, there is hyperplasia of the dermal nerves and that these reveal evidence of an ultrastructural degeneration. Feuerman et al.,7 in studies by electron microscopy, observed that the Schwann cells had a shinning cytoplasma with few mitochondria, no endoplasmatic reticulum, few irregular vacuoles, and mesaxons of normal aspect. The axons varied widely in diameter; there were small axons of normal appearance and other large "empty" axons. Similar findings were observed later by Runne & Orfanos;14 however, in three other series,8,9,54 no neuroma formation was observed.
Lindley & Payne 54 reported that neural hyperplasia is neither essential, nor a common finding in PN, having observed such alteration only in five of 26 specimens. However, the nerve count was statistically increased in PN when compared with negative controls (normal skin) and positive controls (specimens with a finding of unspecific chronic dermatitis). The authors share the opinion of Doyle et al.8 that neural hyperplasia, as well as epidermal and vascular hyperplasia are the result, not the cause, of chronic trauma.
Miyauchi & Uehara55 report that hair follicles are often found in the center of PN lesions and that the inflammatory dermal infiltrate is often placed in a triangular form on the upper and medium dermis around these follicles.
Since PN often seems to be triggered or aggravated by a subjacent pruriginous disease, carrying out routine examinations (complete blood cell count, glycemia, liver transaminases, urea, creatinine, chest X-rays, among others) are suggested.10
Zelickson et al.29 recommend contact tests as a rational part of the PN patient's evaluation. If relevant discovered allergens are really avoided, rewarding results may be obtained.
Although many authors state that PN and lichen simplex chronicus (LSC) are part of the same disease spectrum,9,17,28,54-57 others consider them as distinct entities.20,21,55
Miyauchi & Uehara55 state that PN may be distinguished from LSC, both through clinical and histopathological aspects. In LSC, plaques at the nape of the neck are often present, while in PN there are nodules mainly in limbs and trunk. In histopathology, the distribution of the inflammatory infiltrate is different in the two entities: in LSC it is distributed uniformly over the superficial dermis parallel to the underlying epidermis, while in PN it has a triangular arrangement from the superficial to the medium dermis.
Lichen planus hypertrophicus may be erroneously diagnosed as PN if attention is not focused on its violet color, almost always present, and if typical cutaneous and oral mucosa lesions are not found.10
Despite its rareness, the differential diagnosis with pemphigoid nodularis, described by Yung et al., must be remembered.58 This clinical picture is similar to PN, however, when using direct immunofluorescence, typical findings of bullous pemphigoid, such as C3 and IgG depositions at the basal epidermal level are observed. The report of previous bullae by the patient calls attention to this diagnosis. There are several additional reports of cases in the literature until now.59-65
Epidermolysis bullosa pruriginosa, a form of dystrophic epidermolysis bullosa (dominant or recessive) may cause lesions similar to PN. However, the possibility of PN is excluded by the presence of bullous lesions induced by the trauma, milia, ungueal dystrophy and, in some cases, albopapuloid lesions on the trunk.66
Multiple keratoacanthoma should be mentioned as a differential diagnosis and also PN can be clinically very similar to cases of angiolymphoid hyperplasia with disseminated lesions,67 atypical presentations of botryomycosis68 and disseminated cutaneous cytomegalovirosis in HIV-positive patients69 and also epidermal cysts.70
PN is notoriously resistant to therapy. Once the cycle of pruritus-excoriation-pruritus begins, it is difficult to be stopped. General measures may be taken, such as trimming of the fingernails to diminish their scratching potential, and hospitalization to allow better observation of the patient.10
Topical agents recommended include: emollients, menthol, tar, corticosteroids and occlusion with bandaging (with or without steroids).10
Emollients are important, since the xerosis almost always worsens the pruritus. Anti-pruritic and refreshing agents, such as menthol, may be added to the emollient, giving the patient a comfortable sensation of freshness. Sensibilizating topical anesthetics agents, such as benzocaine, should be avoided.10 Moderate topical corticosteroids may be used, provided with caution to avoid cutaneous atrophy.10 Occlusive bandages are useful in the interruption of the pruritus-excoriation-pruritus cycle, both by their physical presence, as well as by the reduction of pain perception, because they produce a low environmental oxygen tension in the lesions, leading to a reduced production of E2 prostaglandin, a known painful inflammatory inducer.71
Intralesional corticosteroids, such as dexametasone or triamcinolone suspensions, may be employed with care to not produce side effects (atrophy) and/or undesirable systemic effects.10
Tupker et al.72 used topical capsaicin, 0.025%, five times a day in the treatment of PN cases, chronic prurigo and circumscribed neurodermitis. It is believed that this substance, derived from red pepper excites the non-mielynized sensorial neurons to liberate substance P, an important transmitter for signals of pruritus and pain, and probably other neuropeptides. Its repeated application would induce their depletion, followed by desensibilization of the C-type neurons. The results were encouraging as to the reduction of pruritus, and the lesions disappeared completely in two of three PN patients.
Oral antihistamines are an alternative for the treatment, especially useful when going to bed, when the absence of distractions from daily activities almost always lead to an increase in pruritus and when higher doses may be used, because of the better tolerability. Sedatives and tranquilizers have been suggested by some authors.10,73
Hindson et al.74 reported a surprising lesion regression in a female middle-aged patient, with the use of benoxaprofen (a non-steroid anti-inflammatory agent) for treatment of a concurrent osteoarthritis.
Occasionally, a short period of systemic therapy with corticosteroids may be indicated.10
Localized phototherapy and photochemotherapy (PUVA), topically applied, have already been used successfully.10,75,76
Shelley,77 in his review on therapy of prurigo, proposed the use of maintenance antibiotic therapy on a long-term basis. Erythromycin is especially recommended as being effective. It is difficult however to propose a mechanism action for this therapy.
Clofazimine was used with a dosage of 300 mg/day for a period of six months in a PN patient refractory to conventional therapy. However, ten months after suspending the drug, the patient presented weight loss and gastrointestinal side effects that improved slightly with the beginning of a gluten-free diet, and presenting relapse a year later. At laparotomy, all tissues stainted yellow-orange, and the histologic examination demonstrated crystal deposits in the chorion of intestinal villi and mesenteric lymph nodes.78
In 1973, Mattos79 reported for the first time a successful PN treatment with thalidomide, a derivative of glutamic acid. Since then, the medication is being used in PN cases refractory to conventional treatment. Winkelmann80 et al. observed that, in-patients with thalidomide administration, the resolution of the pruritus was obtained within weeks and involution of the nodular lesions in several months. In those where the medication was withdrawn, the pruritus occurred after two months and became intense around three to four months, yielding again after restarting the treatment. The authors suggest that a long-term benefit may be obtained in about six months and state that a 200mg daily dose is adequate for the treatment, although mentioning that Mattos79 and Sheskin81 would have used higher doses.
Thalidomide was used successfully in a refractory PN patient associated to photo-sensibility and advanced stage of AIDS.48 For some authors, this drug comes as a promising therapeutic option in these patients, because it is not an immunosupressor.
The use of thalidomide in PN must be carefully evaluated. It must never be used in women during the fertile period who do not use a satisfactory contraceptive method, because of the risk of teratogenesis. Chronic toxicity in adult humans seems infrequent, however a number of cases of polyneuritis associated with long-term treatment have been reported.82 Symptoms are mainly of a sensorial nature (painful paresthesia), but may include muscular weakness in a later stage. The incidence of thalidomide-induced neuropathy has not been well defined; and in the few retrospective studies already conducted, the rates varied from 1 to 50%, based on symptoms and clinical examinations.82,83 Clemmensen et al.84 also observed a high neuropathy rate in their patients and attributed the fact to having made exhaustive examinations concerning clinic and electromyography. In the Johnke & Zachariae series,85 the neuropathy was the reason for the suspension of thalidomide in five of 22 patients (22%) with PN. Bielsa et al.86 reported erythroderma during the use of thalidomide in two patients with chronic renal insufficiency. The authors emphasized the possibility of a severe cutaneous hypersensitivity reaction due to the drug and speculate about the role performed by the renal insufficiency present in both cases. The mechanism of thalidomide action in PN is still much in discussion; seeming reasonable to assume that the drug acts through its central sedative effect, causing a reduction of peripheral stimuli perception, such as pruritus. Consequently, an interruption of the pruritus-excoriation cycle would occur. However this does not explain why other sedatives have not been efficient. On the other hand, there may exist a peripheral action in the neural tissue in the PN lesions. The medication seems to have an action on the immune system, not yet well understood.82
Berth-Jones al.87 reported a case of cyclosporin use, in doses of 3-4.5 mg/kg/day in two patients with severe PN, for periods of 36 and 24 weeks, respectively. In both cases, there was a marked reduction of the pruritus after two weeks. In one of the patients there was a considerable although incomplete response, and in the other, total resolution of the disease was achieved. In one of the patients an increase of creatinine during treatment was observed. With the suspension of the drug, there was relapse in both patients.
There is a scarcity of literature concerning the use of liquid nitrogen cryotherapy in the treatment of PN. Graham88 listed cryotherapy as a therapeutic agent useful in PN, but did not discuss the duration of the freezing, if bullae was produced, or how many freeze-thaw cycles were applied. Waldinger et al.89 obtained a significant result in their patients only when the bullae was produced.
The number of simultaneously treated nodules and the duration of cryotherapy for individual nodules must be determined for each patient. If numerous nodules are treated at the same extremity and at the same time, the edema and resulting pain may be considerable and with long duration. Besides, black-skinned patients must be aware of possible residual hypopigmentation following this therapeutic method.
The mechanism of
the initial eradication of the nodules with cryotherapy is due to the production
of a blister with subsequent healing. The continued absence of pruritus after
cryotherapy may be due to the resolution of the lesions, but may be caused by
sensorial nervous damage.89 Stoll et al.90 obtained good results in treatment
of PN with the combined use of cryosurgery and intralesional steroids plus lidocaine
Hirsche-Scholtz et al.13 reported the use of arotinoid acid (Ro-137410) in the treatment of PN lesions with regression of the nodules in those sites where retinoid dermatitis developed.
The nodular prurigo is a relatively uncommon idiopathic condition. Although well defined from the clinical and histopathological standpoint, it is frequently considered as a variation of eczema. The characteristic lesions are pruriginous nodules distributed mainly on extensor aspects of the limbs; and, in severe cases, also on the trunk. It is probable that subjacent local diseases, systemic or of a psychic nature perform important roles in its genesis. In fact, identical lesions have been observed in atopic dermatitis and bullous pemphigoid, suggesting that they may represent an induced reaction pattern by an ample variety of stimuli. The disease causes considerable anxiety mainly as a result of the intense pruritus and constant desire to scratch the lesions. Its spontaneous regression is rare and relapse to the treatment is common, despite several therapeutic options available. Thalidomide is now considered the treatment of choice, even as an option for affected AIDS patients, because it is not an immunosupressor. Its risks and benefits must nevertheless be seriously evaluated because of the possibility of teratogenesis and other less severe adverse effects.
1. Hyde JN, Montgomery FH. A practical treatise on diseases of the skin for the use of students and practitioners. Philadelphia: Lea & Febiger, 1909;174-175.
2. Hardaway WA. A case of multiple tumors of the skin accompanied by intense itching. Arch Dermatol 1880;6:129-132.
3. Brocq LAJ. Lichen obtusus corneus. Prat Dermatol 1900;3:201.
4. Pautrier LM. Le néurome de la lichénification circonscrite nodulaire chronique (lichen ruber obtusus corné, prurigo nodularis). Ann Dermatol Syph 1934;7:897-919.
5. Pérez RM, Maruri CA. Polynévrite cutanée nodulaire chronique allergique. Ann Dermatol Syph 1949;9:623-648.
6. Cowan MA. Neurohistological changes in prurigo nodularis. Arch Dermatol 1964;89:734-738.
7. Feuerman EJ, Sandbank M. Prurigo nodularis: histological and electron microscopical study. Arch Dermatol 1975;111:1472-1477.
8. Doyle JA, Connolly SM, Hunziker N, Winkelmann RK. Prurigo nodularis: a reappraisal of the clinical and histologic features. J Cutan Pathol 1979;6:392-403.
9. Payne R, Wilkinson JD, McKee PH, Jurecka W, Black MM. Nodular prurigo - a clinicopathological study of 46 patients. Br J Dermatol 1985;113:431-439.
10. Jorizzo JL. Prurigo: a clinical review. J Am Acad Dermatol 1981;4:723-728.
11. Schelnitz LS, Paller AS. Hodgkin's disease manifesting as prurigo nodularis. Pediatr Dermatol 1990;7:136-139.
12. Gomes PA, Duarte AA, Oliveira Filho J, Cucé LC. Prurigo nodular de Hyde na infância. An bras Dermatol 1994;69:301-303.
13. Hirschel-Scholz S, Salomon D, Merot Y, Saurat J-H. Anetodermic prurigo nodularis (with Pautrier's neuroma) responsive to arotinoid acid. J Am Acad Dermatol 1991;25:437-442.
14. Runne U, Orfanos CE. Cutaneous neural proliferation in highly pruritic lesions of chronic prurigo. Arch Dermatol 1977;113:787-791.
15. Wollina U, Simon D, Knopf B. Prurigo nodularis Hyde - Bevorzugung der Hautspaltlinien. Dermatol Mon Schr 1990;176:469-473.
16. Weyers W. Lichen amyloidosus. Krankheitsentitat oder Kratzeffekt. Hautarzt 1995;46:165-172.
17. Pillsbury DM. Eczema. In: Moschella SL, Pillsbury DM, Hurley HJ, eds. Dermatology. Philadelphia: W.B. Saunders, 1975:293.
18. Vaalasti A, Suomalainen H, Rechardt L. Calcitonin gene-related peptide immunoreactivity in prurigo nodularis: a comparative study with neurodermatitis circunscripta. Br J Dermatol 1989;120:619-623.
19. Molina FA, Burrows NP, Jones RR, Polak JM. Increased sensory neuropeptides in nodular prurigo: a quantitative immunohistochemical analysis. Br J Dermatol 1992;127:344-351.
20. Harris B, Harris K, Penneys NS. Demonstration by S-100 protein staining of increased numbers of nerves in the papillary dermis of patients with prurigo nodularis. J Am Acad Dermatol 1992;26:56-58.
21. Nahass GT, Penneys NS. Merkel cells and prurigo nodularis. J Am Acad Dermatol 1994;31:86-88.
22. Perez GL, Peters MS, Reda AM, Butterfield JH, Peterson EA, Leiferman KM. Mast cells, neutrophils, and eosinophils in prurigo nodularis. Arch Dermatol 1993;129:861-5.
23. Juhlin L, Venge P. Eosinophilic cationic protein (ECP) in skin disorders. Acta Derm Venereol (Stockh) 1991;71:495-501.
24. Geary WA, Cooper PH. Proliferating cell nuclear antigen (PCNA) in common epidermal lesions. J Cutan Pathol 1992;19:458-468.
25. Juhlin L, Magnoldo T, Darmon M. Expression of loricrin in skin disorders. Acta Derm Venereol (Stockh) 1992;72:407-409.
26. Miyachi Y, Okamoto H, Furukawa F, Imamura S. Prurigo nodularis: a possible relationship to atopy. J Dermatol (Tokyo) 1980;7:281-283.
27. Tanaka M, Aiba S, Matsumura N, Aoyama H, Tagami H. Prurigo nodularis consists of two distinct forms: early-onset atopic and late-onset non-atopic. Dermatology 1995;190:269-276.
28. Shaffer B, Beerman H. Lichen simplex chronicus and its variants: a discussion of certain psychodynamic mechanisms and clinical and histopathologic correlations. Arch Dermatol Syphilol 1951;64:340-351.
29. Zelickson BD, McEvoy MT, Fransway AF. Patch testing in prurigo nodularis. Contact Dermatitis 1989;20:321-325.
30. Heng MC, Allen SG, Kim A, Lieberman J. Alpha-1 antitrypsin deficiency in a patient with widespread prurigo nodularis. Australas J Dermatol 1991;32:151-157.
31. Mattila JO, Vornanen M, Vaara J, Katila M-L. Mycobacteria in prurigo nodularis: the cause or a consequence? J Am Acad Dermatol 1996;34:224-228.
32. Boer J, Smeenk G. Nodular prurigo-like eruptions induced by etretinate. Br J Dermatol 1987;116:271-274.
33. Iijima S. Prurigo nodularis. Tohoku J Exp Med 1951;54:73-80.
34. Rien BE, Lemont H, Cohen RS. Prurigo nodularis: an association with uremia. J Am Podiatr Assoc 1982;72:321-323.
35. Brown MA, George CRP, Dunstan CR, Kalowski S, Corrigan AB. Prurigo nodularis and aluminum overload in maintenance haemodialysis. Lancet 1994;340:48.
36. Wells GC. Skin disorders in relation to malabsorption. Br Med J 1962;4:937-943.
37. Howell R. Exudative nummular prurigo with idiopathic malabsorption syndrome. Br J Dermatol 1967;79:357.
38. McKenzie AW, Stubbing DG, Elvy BL. Prurigo nodularis and gluten enteropathy. Br J Dermatol 1976;95:89-92.
39. Goodwin PG. Nodular prurigo associated with gluten enteropathy. Proc R Soc Med 1977;70:140-141.
40. Suárez C, Pereda JM, Moreno LM, Garcia-Gonzaléz F, Gómez-Orbaneja J. Prurigo nodularis associated with malabsorption. Dermatologica 1984;169:211-214.
41. Cole HN. The cutaneous manifestations of Hodgkin's disease. JAMA 1917;69:341-346.
42. Shilmire B. Hodgkin's disease of the skin. South Med J 1925;18:511-518.
43. Fina L, Grimalt R, Berti E. Nodular prurigo associated with Hodgkin's disease. Dermatologica 1991;182:243-246.
44. Funaki M, Ohno T, Dekio S, et al. Prurigo nodularis associated with advanced gastric cancer: report of a case. J Dermatol (Tokyo) 1996;23:703-707.
45. Seeburger J, Anderon-Wilms N, Jacobs R. Lennert's lymphoma presenting as prurigo nodularis. Cutis 1993;51:355-358.
46. Anzala AO, Wanbugu P, Bosire M, Ngugi EN, Waiyaki P, Plummer FA. The rate of development of HIV-1 related illness in women with a known duration of infection. AIDS 1990;6:143 (abst.).
47. Wanbugu P, Plummer FA, Anzala AO, Gilks C, Bosire M, Ngugi EN. Clinical manifestations of HIV-1 infection among women working as prostitutes in Nairobi. AIDS 1990;6:260 (abst.).
48. Berger TG, Hoffman C, Thieberg MD. Prurigo nodularis and photosensitivity in AIDS: treatment with thalidomide. J Am Acad Dermatol 1995;33(5 pt 1):837-838.
49. Kundu A, Wade AAH, Ilchyshyn A. Prurigo nodularis in an HIV positive man. Genitourin Med 1995;71:129-135.
50. Roenigk RK, Dahl MV. Bullous pemphigoid and prurigo nodularis. J Am Acad Dermatol 1986;14:944-947.
51. Borradori L, Prost C, Wolkenstein P, Bernard P, Baccard M, Morel P. Localized pretibial pemphigoid and pemphigoid nodularis. J Am Acad Dermatol 1992;27:863-867.
52. Lever WF, Schaumburg-Lever G. Histopathology of the skin. 7th ed. Philadelphia: JB Lippincott, 1990:155-156.
53. Wong E, MacDonald DM. Localized subepidermal fibrin deposition - a histopathologic feature of friction induced cutaneous lesions. Clin Exp Dermatol 1982;7:499-503.
54. Lindley RP, Payne CMER. Neural hyperplasia is not a diagnostic requisite in nodular prurigo. J Cutan Pathol 1989;16:14-18.
55. Miyauchi H, Uehara M. Follicular occurrence of prurigo nodularis. J Cutan Pathol 1988;15:208-211.
56. Burton JL, Rook A, Wilkinson DS. Eczema, lichen simplex, erythroderma and prurigo. In: Rook A, Wilkinson DS, Ebling FJG, Champion RH, Burton JL, eds. Textbook of dermatology. 4th ed. Oxford: Blackwell Scientific, 1986;367-418.
57. Ackerman AB. Histologic diagnosis of inflammatory skin diseases. Philadelphia: Lea & Febiger, 1978:256.
58. Yung CW Soltani K, Lorincz AL. Pemphigoid nodularis. J Am Acad Dermatol 1981;5:54-60
59. Massa MC, Conolly SM. Bullous pemphigoid with features of prurigo nodularis. Arch Dermatol 1982;118:937-939.
60. Tani M, Murata Y, Masaki H. Pemphigoid nodularis. J Am Acad Dermatol 1989;21:1099-1104.
61. Borradori L, Rybojad M, Verola O, Flageul B, Puissant A, Morel P. Pemphigoid nodularis. Arch Dermatol 1990;126:1522-1523.
62. Ross JS, Mackee PH, Smith NP, et al. Unusual variants of pemphigoid: from pruritus to pemphigoid nodularis. J Cutan Pathol 1992;19:212-216.
63. Gallo R, Parodi A, Rebora A. Pemphigoid nodularis. Br J Dermatol 1993;129:744-745.
64. Bourke JF, Berth-Jones J, Gawkrodger DJ, Burns DA. Pemphigoid nodularis: a report of two cases. Clin Exp Dermatol 1994;19:496-499.
65. Tamada Y, Yokochi K, Ushitani Y, et al. Pemphigoid nodularis: a case with 230KDa hemidesmosomes antigen associated with bullous pemphigoid antigen. J Dermatol (Tokyo) 1995;22:201-204.
66. McGrath JA, Schofield OM, Eady RA. Epidermolysis bullosa pruriginosa: dystrophic epidermolysis bullosa with distinctive clinicopathological features. Br J Dermatol 1994;130:617-625.
67. Amagai N, Stolar E, Williams CM. Unusual widespread type of angiolymphoid hyperplasia with eosinophilia mimicking prurigo nodularis. J Dermatol (Tokyo) 1993;20:660-661.
68. Salvemini JN, Baldwin HE. Bothyomycosis in a patient with acquired immunodeficiency syndrome. Cutis 1995;56:158-160.
69. Chiewchanvit S, Thamprasert K, Siriunkgul S. Disseminated cutaneous cytomegalic inclusion disease resembling Prurigo nodularis in a HIV-infected patient: a case report and literature review. J Med Assoc Thai 1993;76:581-584.
70. Park SK, Lee JY, Kim YH, Kim SY, Cho BK, Houh W. Molluscum contagiosum occurring in an epidermal cyst - report of 3 cases. J Dermatol (Tokyo) 1992;19:119-121.
71. Meyers LN. Use of occlusive membrane in the treatment of prurigo nodularis. Int J Dermatol 1989;28:275-276.
72. Tupker RA, Coenraads PJ, Van der Meer JB. Treatment of prurigo nodularis, chronic prurigo and neurodermatitis circunscripta with topical capsaicin. Acta Derm Venereol (Stockh) 1992;72:463-465.
73. Griether A. On the different forms of prurigo: pruritus-prurigo. Curr Probl Dermatol 1970;3:1-30.
74. Hindson C, Lawlor F, Wacks H. Treatment of nodular prurigo with benoxaprofen. Brit J Dermatol 1982;107:369.
75. Vaatainen N, Hannuksela M, Karvonen J. Local photochemotherapy in nodular prurigo. Acta Derm Venereol (Stockh) 1979;59:544-547.
76. Hann SY, Cho MY, Park Y-K. UV treatment of generalized prurigo nodularis. Int J Dermatol 1990;29:436-437.
77. Shelley WB. Consultations in Dermatology, II. Philadelphia: W.B. Saunders, 1974;47.
78. Belaube P, Devaux J, Pizzi M, Boutboul R, Privat Y. Small bowel deposition of crystals associated with the use of clofazimine in the treatment of prurigo nodularis. Int J Lep 1983;51:328-330.
79. Mattos O. Prurigo nodular de Hyde tratado com talidomida. Bol Div Nac Lepra 1973;32:71-77.
80. Winkelmann RK, Connolly SM, Doyle JA, Gonçalves AP. Thalidomide treatment of prurigo nodularis. Acta Derm Venereol (Stockh) 1984;64:412-417.
81. Sheskin J. Therapeutische Erfahrungen ber den einfluss der thalidomids bei der leprareaktion. Hautarzt 1975;26:1-5.
82. Van Den Broek H. Treatment of prurigo nodularis. Acta Derm Venereol (Stockh) 1984;64:412-417.
83. Fullerton PM, O'Sullivan DJ. Thalidomide neuropathy: a clinical, electrophysiological and histological follow-up study. J Neurol Neurosurg Psychiatry 1968;31:543-551.
84. Clemmensen OJ, Olsen PZ, Andersen KE. Thalidomide neurotoxicity. Arch Dermatol 1984;120:338-341.
85. Johnke H, Zachariae H. Thalidomid be handling af prurigo nodularis. Ugeskr Laeger 1993;155:3028-3030.
86. Bielsa I, Teixido J, Ribera M, Fernandiz C. Erythroderma due to thalidomide: report of two cases. Dermatology 1994;189:179-181.
87. Berth-Jones J, Smith SG, Graham-Brown RAC. Nodular prurigo responds to cyclosporin. Brit J Dermatol 1995;132:795-799.
88. Graham GF. Cryosurgery in treatment of acne and specific cutaneous neoplasia, In: Zacarian SA, ed. Cryosurgical Advances in Dermatology and tumors of the head and neck. Springfield, Charles C Thomas, 1977;74-97.
89. Waldinger TP, Wong RC, Taylor WB, Voorhees JJ. Cryotherapy improves prurigo nodularis. Arch Dermatol 1984;120:1598-1600.
90. Stoll DM, Fields JP, King LE. Treatment of prurigo nodularis: use of cryosurgery and intralesional steroids plus lidocaine. J Dermatol Surg Oncol 1983;9:922-924.