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Dermatologic Therapy, Vol. 21, 2008, 4246 Printed in the United States All rights reserved

Copyright Blackwell Publishing, Inc., 2008

DERMATOLOGIC THERAPY

ISSN 1396-0296

Blackwell Publishing Inc

Prurigo nodularis and lichen simplex chronicus

T

ORELLO

L

OTTI

, G

IONATA

B

UGGIANI

& F

RANCESCA

P

RIGNANO

Department of Dermatological Sciences, University of Florence, Florence, Italy

ABSTRACT:

Emotional tensions in predisposed subjects may play a key role in inducing a pruriticsensation, leading to a scratching that, becoming a self-perpetuating pathomechanism, may representthe main feature of two distinct cutaneous clinical entities: prurigo nodularis and lichen simplexchronicus. Psychogenic factors play a relevant role in both conditions, and they are often associatedwith depression and dissociative experiences. Hence, the importance of the evaluation of thesepatients from the point of view of psychodermatology, which may analyze the relationship betweenskin disease and psychological factors. Patients with real or perceived imperfections in particularareas of the body (face, scalp, hands, and genital area) are more prone to psychologic distress,whereas cutaneous diseases may lead to experience a heightened level of distress. As psychosomaticfactors have been estimated to be present in at least one-third of dermatologic patients, effectivemanagement of skin conditions involves consideration of the associated emotional factors.

KEYWORDS:

lichen simplex chronicus, management, prurigo nodularis, psychodermatology

Introduction

According to a psychosomatic perspective usuallyagreed upon in the scientific community, emo-tional tensions in predisposed subjects may playa key role in inducing itch, thus provokingscratch. This phenomenon can become a self-perpetuating pathomechanism bringing to dis-tinct cutaneous clinical entities that includeprurigo nodularis (PN) and lichen simplexchronicus (LSC).

Prurigo nodularis is a dermatologic conditioncharacterized by the presence of papules andnodules with primary intense pruritus. PN (chroniccircumscribed nodular lichenification, Pickersnodules) can occur at all ages and equally in bothsexes. It presents with hard nodule(s) 15 cm indiameter, with a warty, excoriated, pigmented darkred surface with central crusts, usually surroundedby an irregular hyperpigmented ring (FIG. 1). Theextensor area of the limbs, face, and trunk areusually affected by the lesions, which may leave

scars when spontaneously regress (FIG. 2). Itch isintense, and severe crises can be triggered byemotional stress.

Lichen simplex chronicus (LSC) is a skin disordercharacterized by lichenification of the skin as aresult of primary excessive scratching (FIG. 3).LSC (circumscribed neurodermatitis) is character-ized by a central lichenificated plaque thickenedand often hyperpigmented, usually surroundedby lichenoid papules and, along the borders withsurrounding normal skin, by an indefinite zone ofslight thickening. The most common sites are theneck (sides), ankles, scalp, vulva, pubis, scrotum,and extensor forearms. The peak of incidence isbetween 35 and 50 years of age, and women aremore affected than men (F:M

=

2:1).Lichen simplex chronicus is in the nomencla-

ture differentiated by other forms of secondarylichenification, which usually complicate persi-stent itching skin lesions of different types, but theborderline is sometimes tenuous. Variants (i.e., thegiant lichenification of Pautrier, of the genitocruralregion, and the so-called pebbly lichenification ofatopic subjects) have been described. Itch is thepredominant symptom. It is characterized byparoxystical attacks, which are intensely scratchedwith great satisfaction, followed by a refractory

Address correspondence and reprint requests to: Torello Lotti, MD, Department of Dermatological Sciences, University of Florence, Via Lorenzo il Magnifico, 104, 50129 Florence, Italy, or email: tlotti@unifi.it.

Pruriginous conditions

43

period of 15 hours and then by another attackof pruritus. Usually, scratching is continued alsoin the refractory period, provoking clear skinsores, especially when severe psychologic stressis experienced.

In both PN and LSC, pruritus is the main sym-ptom, and the persistence and the progression ofskin lesions are strictly correlated to scratchingand rubbing. It is widely known that the definitionof pruritus is at least unsatisfactory and we stillaccept to describe it as a sensation that, if suffi-ciently strong, will provoke scratching or thedesire to scratch (1,2). In most of the dermato-logic diseases the symptom pruritus is associ-ated and is therefore strictly linked to the maindermatosis. In other cases, pruritus becomes aconsequence of the primary cutaneous diseaseas a sign of progression or chronicization of thedermatosis. In both PN and LSC the underlyingstimulus (and the only apparent cause) and themost important symptom is pruritus.

The first definition of LSC was introduced byVidal and then further described by Brocq; Hard-way reported a skin condition characterized bymultiple nodular lesions and pruritus. Hyde lateron defined this condition as PN (3).

Some authors (3) use the definition of PN assynonymous of LSC but according to others, theyare two distinct clinical entities characterized byhaving both pruritus as stimulus. Hypothesestrying to explain pruritus related to PN and LSCfocus on internal medical disorders, associateddermatoses, and above all psychologic aspects.The most frequent general related disorders reportedin the literature are renal failure or chronicobstructive biliary disease, Hodgkins lymphoma,hyperthyroidism, polycythemia rubra vera, gluten-sensitive enteropathy; triggering dermatoses areatopic dermatitis, allergic contact dermatitis,stasis dermatitis, and insect bites.

Psychogenic factors may play a relevant role inboth PN and LSC; the evaluation of the psychiatricprofile has evidenced that they are often associ-ated with depression and dissociative experiences(4,5). The field of psychodermatology has developedbecause of an increased interest in understandingthe relationship between skin disease and variouspsychologic factors (6). Patients with real andperceived imperfections in important image areas(face, scalp, hands, and genital area) are more proneto psychologic distress. Moreover, people withcutaneous diseases experience a heightened levelof distress, as measured by the General HealthQuestionnaire and structured diagnostic interviews(7,8). As psychosomatic factors in dermatologicdiseases have been estimated to be present in atleast one-third of dermatologic patients, effec-tive management of the skin condition involvesconsideration of the associated emotional factors(8,9).

FIG. 1. Prurigo nodularis. Two hyperpigmented noduleswith clear-cut margins; the one on the right with a centralcrust.

FIG. 2. Prurigo nodularis. Many nodules of different colorand size, mainly localized on extensor surface of forearmsand residual scarring lesions.

FIG. 3. Lichen simplex chronicus. Area of lichenificationdue to chronic scratching of the upper side of the thigh.

Lotti

et al.

44

Histopathology and pathogenesis

The histopathological features of PN are epidermalhyperplasia with orthokeratosis, focal parakeratosisand irregular acanthosis, mild to severe hyper-granulosis and proliferation of Swann cells, andneural hyperplasia. An increased number ofMerkel cells in the epidermis has been shown (10).The inflammatory infiltrate in the dermis is con-stituted mainly by lymphocytes, mast cells, histio-cytes, and occasionally eosinophils (11,12). Mastcells in PN are characterized by a more dendriticshape as compared to normal skin, where they arenormally roundish or elongated, are more numer-ous, and are closely linked to nerve endings. Themorphology of these cells and the neighborhoodto nerve endings correlates with an increase innerve growth factor (NGF) release (12,13) and toall mediators of itch produced by mast cells as:histamine, tryptase, leukotrienes, prostaglandins,interleukins 2,4,6 (1417). In addition, eosinophils,which are increased in the dermis, contain highlevels of eosinophil cationic protein and eosinophil-derived neurotoxin/eosinophil protein x. Bothproteins are able to degranulate mast cells (16).

The histopathological features in lichen simplexare epidermal hyperplasia, orthokeratosis, andhypergranulosis with a regular elongation of therete ridges. There is a perivascular infiltrate oflymphocytes and occasionally of macrophages.The macrophages are not clearly dendritic as inPN and much less numerous. Moreover, in LSCthere is no neural hyperplasia and abundancy ofNGF and lack of positive immunostaining for NGFreceptor mediators of pruritus as in PN (3,14).These recent investigations not only further con-tribute to differentiate PN from LSC, but provideinteresting data for speculating on the pathogene-sis of the two disorders.

Diagnosis and differential diagnosis

In PN and in LSC, the clinical features are usuallysufficient for diagnosing the disorders. The firststep is to exclude any underlying disease and thento address causes of general pruritus, which canbe monitored by the laboratory (Table 1). Instru-mental evaluation as CT scan and chest X-raysare performed in case of suspicion of lymphoma.Once general causes have been excluded, the mostcommon dermatologic differential diagnoses forPN are: hypertrophic lichen planus, multiple kerato-acanthomas, and pemphigoid nodularis. If there arefew lesions also nodular scabies can be considered.

Lichen simplex chronicus has to be differenti-ated from psoriasis, mycosis fungoides, lichenplanus, and lichen amyloidosis. All these derma-toses can be easily excluded or not according tothe histopathology.

PN and LSC A model for cutaneous psychoneuroimmunology?

Links between mental and affective disorders andthe cutaneous related neuro-immune-endocrinestatus are well described (18), thus supporting thehypothesis that psychologic and social factorsinfluence diseases processes in the skin. The skin,in particular, can be interpreted as the juncture ofthe simultaneous and connected activity of brain,immune system, and the skin itself. In this contextneuropeptides, interleukins, and immune systemmessengers not only are the messengers, but alsothe actors of the specific clinical entities. Surpris-ingly, in front of many papers dealing with generalinteractive models in the area of stress and psy-choneuroimmunologic factors in dermatology, veryfew clinical and experimental studies have inves-tigated the association of data and well-definedclinical entities. Nevertheless, psychotropic agentsand nonpharmacologic psychotherapeutic inter-ventions may have a strong positive impact onsome dermatoses, including PN and LSC, accord-ing to others experience and that of the presentauthors (1921).

Well-defined clinical entities like PN and LSCprobably represent the optimal area of investiga-tion to understand the psycho-neuro-immuneevents in the human skin.

Management and treatment

Both lichen simplex and PN are frustrating condi-tions (for both patient and dermatologist) to treat,

Table 1. Suggested investigations in prurigonodularis

Blood countRenal functionality (urea, creatinine, and electrolytes)Liver function tests and serology for hepatitisThyroid and parathyroid hormonesTotal serum IgE levelsPatch testHIV test and Mantoux test (if indicated)Skin biopsy

Pruriginous conditions

45

in the absence of any clear underlying association,because of their high resistance to therapy. Thereis an itch-scratch cycle, which is extremely difficultto stop, but moreover, there is a particular psy-chologic state of the patients affected by bothdermatoses (14,15). Therefore the therapeutic strat-egies (21) other than pharmacologic are extremelyimportant.

Topical aspecific antipruritic agents as 1% mentholand phenol in base creams, recommended in the past,are not very helpful. Potent topical glucocorticoidcreams or ointments as betamethasone dipropionate(under occlusion) or intralesional glucocorticoidssuch as triamcinolone acetonide are often suc-cessfully employed. Topical application of capsaicin(0.0250.1%), which is able to prevent the accu-mulation of neuropeptides in unmyelinated poly-modal C-type and small myelinated A-delta typecutaneous nerves (22), can be effective in the veryearly manifestations. Topical tacrolimus has provedto be effective in LSC (23).

In diffuse and/or resistant forms of PN, ultravi-olet-based therapy utilizes UVB (both broadbandand narrowband) and UVA; narrowband UVB seemsto be more effective and less dangerous thenPUVA which is slowly loosing the therapeuticprevalence of the past. In resistant forms of PN,cyclosporine reduces the severity of pruritus byinhibiting lymphokine transcription and lympho-cytes activation and proliferation. The dosagesshould not be lower than 4 mg/kg/day for periodsnot shorter than 6 months. Thalidomide andnaltrexone can also be effective in recalcitrant,diffuse forms of PN. Thalidomide reduces poly-morphonuclear leukocyte chemotaxis and selec-tively inhibits TNF-alpha production by enhancingdegradation of TNF-alpha mRNA (24) thus inter-acting with the described patho-mechanisms. Theantipruritic effects of naltrexone are apparentlythe result of its antagonizing activity on centraland peripheral opiate receptors. There are reports(25) on the efficacy of etretinate (5075 mg/day)in reducing pruritus even if the specific mecha-nisms of action are not well documented.

Next to the pharmacologic treatment, psycho-somatic interventions can be suggested. One ofthe best documented strategy is the biofeedback.As reported by Shenefelt (26) in cutaneous disor-ders with documented autonomic nervous systemcomponent, biofeedback with or without associ-ated hypnosis can be helpful. With trainings, indi-viduals can consciously experience how to alter theautonomic response and with enough repetitionthey may establish new habit patterns, possiblyavoiding, e.g., scratching and rubbing.

The supportive counseling comprises manydifferent psychologic interventions that the physi-cian can apply to pay attention to the distur-bances reported by the patient. Approaches rangefrom reassurance to clarification regarding theexact nature of the disease, to the point of trigger-ing called flash (18). In such a case, the physi-cian can succeed in transmitting a flash ofcomprehension to the patient. Early rationalclarification of the symptoms can prevent thedevelopment of an obsessive vicious circle regard-ing illness and the consequent chronicity of theclinical pattern. Also, the cognitive-behavioraltherapies have given good results in LSC and PN(27). These methods have the aim to modifybehaviors that are considered nonadaptive to theindividual. Moreover, they draw in part on thecognitive therapies of identifying dysfunctionalnegative self-talk or reframing the thought pictureby offering a new positive perspective.

Conclusions

Patients affected by dermatologic diseases as LSCand PN are challenging patients for the dermato-logist, because they usually need not onlydermatologic problem-solving skills to managethe physical care demands, but also emotion-regulating skills to handle their emotional disease.Moreover, in this view, the collaboration with anexpert psychodermatologist or, at least, with apsychotherapist keen in the field of managingdermatologic patients, may result in the optimalmanagement of the patient.

References

1. Bernhard JD. Pruritus. Lancet 1995:

345

: 1584.2. Bernhard JD. Itch and pruritus: what are they and how

should itches be classified? Dermatol Ther 2005:

18

: 288291.

3. Soter NA. Nummular eczema and Lichen simplex chroni-cus/prurigo nodularis. In: Freedberg IM, Eisen AZ, Wolff K,Austen KF, Goldsmith LA, Katz SI, eds. Fitzpatricks derma-tology in general medicine, Vol. 1, 6th edn. New York:McGraw-Hill USA, 2003: 11941198.

4. Konuk N, Koca R, Atik L, et al. Psychopathology, depressionand dissociative experiences in patients with lichen sim-plex chronicus. Gen Hosp Psychiatry 2007:

29

: 232235.5. Krishnan A, Koo J. Psyche, opioids, and itch: therapeutic

consequences. Dermatol Ther 2005:

18

: 314322.6. Koo J, Do JH, Lee CS. Psychodermatology. J Am Acad

Dermatol 2000:

43

: 848853.7. Hughes J, Barraclough B, Hamblin L, et al. Psychiatric

symptoms in dermatology patients. Br J Psychiatry 1983:

143

: 5154.

Lotti

et al.

46

8. Panconesi E. Psychosomatic dermatology. Clin Dermatol1984:

2

: 814.9. Gupta MA, Gupta AK. Psychodermatology: an update. J Am

Acad Dermatol 1996:

34

: 10301046.10. Nahass G, Penneys NS. Merkel cells and prurigo nodularis.

J Am Acad Dermatol 1994:

31

: 8688.11. Weedon D. Tumors of the epidermis. In: Skin pathology,

2nd edn. London: Churchill Livingstone, 2002: 753802.12. Liang Y, Jacobi JA, Marcusson M, Haak-Frendscho M,

Johansson O. Dendritic mast cells in prurigo nodularisskin. Eur J Dermatol 1999:

9

: 297299.13. Liang Y, Marcusson JA, Johansson O. Leight and electron

microscopic observations of p75 nerve growth factorreceptor-immunoreactive dermal nerves in prurigo nodularis.Arch Dermatol Res 1999:

291

: 1421.14. Lee MR, Shumack S. Prurigo nodularis: a review. Australas J

Dermatol 2005:

46

: 211220.15. Stante M, Hanna D, Lotti T. Itch, pain and metaesthetic

sensation. Dermatol Ther 2005:

18

: 308313.16. Schmelz M. Itch mediators and mechanisms. J Dermatol

Sci 2002:

28

: 9196.17. Lotti T, Hautmann G, Panconesi E. Neuropeptides and

skin. J Am Acad Dermatol 1995:

33

: 482496.18. Urpe M, Pallanti S, Lotti T. Psychosomatic factors in derma-

tology. Dermatol Clin 2005:

23

: 609617.

19. Panconesi E. Psychosomatic factors in dermatology: specialperspectives for application in clinical practice. DermatolClin 2005:

23

: 629634.20. Pallanti S, Lotti T, Urpe M. Psychoneuroimmunodermato-

logy: from empiric data to the evolutionary hypothesis.Dermatol Clin 2005:

23

: 695703.21. Urpe M, Buggiani G, Lotti T. Stress and psychoneuroimmu-

nologic factors in dermatology. Dermatol Clin 2005:

23

:609618.

22. Lotti T, Teofoli P, Tsampau D. Treatment of aquagenicpruritus with capsaicin cream. J Am Acad Dermatol 1994e:

30

: 232235.23. Ashoff R, Wozel G. Topical tacrolimus for the treatment of

lichen simlex chronicus. J Dermatolog Treat 2007:

18

: 115117.

24. Wines NY, Cooper AJ, Wines MP. Thalidomide in dermatol-ogy. Australas J Dermatol 2002:

43

: 229240.25. Gip L. Prurigo nodularis (Hyde) trated with Tigason (Abstract).

Dermatologica 1984:

169

: 260.26. Shenefelt PD. Biofeedback, cognitive-behavioral methods,

and hypnosis in dermatology: is it all in your mind? Der-matol Ther 2003:

16

: 114122.27. Phillips KA. Body dysmorphic disorder: diagnosis and

treatment of imagined ugliness. J Clin Psychiatry 1996:

57

:6165.

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